Pyrazole derivatives as plasma kallikrein inhibitors

ABSTRACT

The present invention provides a selection of compounds of formula (I): (I) compositions comprising such compounds; the use of such compounds in therapy (for example in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated); and methods of treating patients with such compounds; wherein R5, R6, R7, A, B, W, X, Y and Z are as defined herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of International PatentApplication No. PCT/GB2017/051546 filed May 31, 2017, which claimspriority from Great Britain Patent Application No. 1609517.6, filed May31, 2016; U.S. Patent Application No. 62/343,363 filed May 31, 2016;Great Britain Patent Application No. 1702044.7 filed Feb. 8, 2017; andU.S. Patent Application No. 62/456,219 filed Feb. 8, 2017, thedisclosures of each of which are incorporated herein by reference intheir entireties for any and all purposes.

This invention relates to enzyme inhibitors that are inhibitors ofplasma kallikrein and to pharmaceutical compositions containing and theuses of, such inhibitors.

BACKGROUND TO THE INVENTION

The heterocyclic derivatives of the present invention are inhibitors ofplasma kallikrein and have a number of therapeutic applications,particularly in the treatment of retinal vascular permeabilityassociated with diabetic retinopathy and diabetic macular edema.

Plasma kallikrein is a trypsin-like serine protease that can liberatekinins from kininogens (see K. D. Bhoola et al., “Kallikrein-KininCascade”, Encyclopedia of Respiratory Medicine, p 483-493; J. W. Bryantet al., “Human plasma kallikrein-kinin system: physiological andbiochemical parameters” Cardiovascular and haematological agents inmedicinal chemistry, 7, p 234-250, 2009; K. D. Bhoola et al.,Pharmacological Rev., 1992, 44, 1; and D. J. Campbell, “Towardsunderstanding the kallikrein-kinin system: insights from the measurementof kinin peptides”, Brazilian Journal of Medical and Biological Research2000, 33, 665-677). It is an essential member of the intrinsic bloodcoagulation cascade although its role in this cascade does not involvethe release of bradykinin or enzymatic cleavage. Plasma prekallikrein isencoded by a single gene and synthesized in the liver. It is secreted byhepatocytes as an inactive plasma prekallikrein that circulates inplasma as a heterodimer complex bound to high molecular weight kininogenwhich is activated to give the active plasma kallikrein. Kinins arepotent mediators of inflammation that act through G protein-coupledreceptors and antagonists of kinins (such as bradykinin antagonists)have previously been investigated as potential therapeutic agents forthe treatment of a number of disorders (F. Marceau and D. Regoli, NatureRev., Drug Discovery, 2004, 3, 845-852).

Plasma kallikrein is thought to play a role in a number of inflammatorydisorders. The major inhibitor of plasma kallikrein is the serpin C1esterase inhibitor. Patients who present with a genetic deficiency in C1esterase inhibitor suffer from hereditary angioedema (HAE) which resultsin intermittent swelling of face, hands, throat, gastro-intestinal tractand genitals. Blisters formed during acute episodes contain high levelsof plasma kallikrein which cleaves high molecular weight kininogenliberating bradykinin leading to increased vascular permeability.Treatment with a large protein plasma kallikrein inhibitor has beenshown to effectively treat HAE by preventing the release of bradykininwhich causes increased vascular permeability (A. Lehmann “Ecallantide(DX-88), a plasma kallikrein inhibitor for the treatment of hereditaryangioedema and the prevention of blood loss in on-pump cardiothoracicsurgery” Expert Opin. Biol. Ther. 8, p 1187-99).

The plasma kallikrein-kinin system is abnormally abundant in patientswith advanced diabetic macular edema. It has been recently publishedthat plasma kallikrein contributes to retinal vascular dysfunctions indiabetic rats (A. Clermont et al. “Plasma kallikrein mediates retinalvascular dysfunction and induces retinal thickening in diabetic rats”Diabetes, 2011, 60, p 1590-98). Furthermore, administration of theplasma kallikrein inhibitor ASP-440 ameliorated both retinal vascularpermeability and retinal blood flow abnormalities in diabetic rats.Therefore a plasma kallikrein inhibitor should have utility as atreatment to reduce retinal vascular permeability associated withdiabetic retinopathy and diabetic macular edema.

Plasma kallikrein also plays a role in blood coagulation. The intrinsiccoagulation cascade may be activated by factor XII (FXII). Once FXII isactivated (to FXIIa), FXIIa triggers fibrin formation through theactivation of factor XI (FXI) thus resulting in blood coagulation.Plasma kallikrein is a key component in the intrinsic coagulationcascade because it activates FXII to FXIIa, thus resulting in theactivation of the intrinsic coagulation pathway. Furthermore, FXIIa alsoactivates further plasma prekallikrein resulting in plasma kallikrein.This results in positive feedback amplification of the plasma kallikreinsystem and the intrinsic coagulation pathway (Tanaka et al. (ThrombosisResearch 2004, 113, 333-339); Bird et al. (Thrombosis and Haemostasis,2012, 107, 1141-50).

Contact of FXII in the blood with negatively charged surfaces (such asthe surfaces of external pipes or the membrane of the oxygenator thatthe blood passes during cardiopulmonary bypass surgery) induces aconformational change in zymogen FXII resulting in a small amount ofactive FXII (FXIIa). The formation of FXIIa triggers the formation ofplasma kallikrein resulting in blood coagulation, as described above.Activation of FXII to FXIIa can also occur in the body by contact withnegatively charged surfaces on various sources (e.g. bacteria duringsepsis, RNA from degrading cells), thus resulting in disseminatedintravascular coagulation (Tanaka et al. (Thrombosis Research 2004, 113,333-339)).

Therefore, inhibition of plasma kallikrein would inhibit the bloodcoagulation cascade described above, and so would be useful in thetreatment of disseminated intravascular coagulation and bloodcoagulation during cardiopulmonary bypass surgery where bloodcoagulation is not desired. For example, Katsuura et al. (ThrombosisResearch, 1996, 82, 361-368) showed that administration of a plasmakallikrein inhibitor, PKSI-527, for LPS-induced disseminatedintravascular coagulation significantly suppressed the decrease inplatelet count and fibrinogen level as well as the increase in FDP levelwhich usually occur in disseminated intravascular coagulation. Bird etal. (Thrombosis and Haemostasis, 2012, 107, 1141-50) showed thatclotting time increased, and thrombosis was significantly reduced inplasma kallikrein-deficient mice. Revenko et al. (Blood, 2011, 118,5302-5311) showed that the reduction of plasma prekallikrein levels inmice using antisense oligonucleotide treatment resulted inantithrombotic effects. Tanaka et al. (Thrombosis Research 2004, 113,333-339) showed that contacting blood with DX-88 (a plasma kallikreininhibitor) resulted in an increase in activated clotting time (ACT).Lehmann et al. (Expert Opin. Biol. Ther. 2008, 1187-99) showed thatEcallantide (a plasma kallikrein inhibitor) was found to delay contactactivated induced coagulation. Lehmann et al. conclude that Ecallantide“had in vitro anticoagulant effects as it inhibited the intrinsicpathway of coagulation by inhibiting plasma kallikrein”.

Plasma kallikrein also plays a role in the inhibition of plateletactivation, and therefore the cessation of bleeding. Platelet activationis one of the earliest steps in hemostasis, which leads to platelet plugformation and the rapid cessation of bleeding following damage to bloodvessels. At the site of vascular injury, the interaction between theexposed collagen and platelets is critical for the retention andactivation of platelets, and the subsequent cessation of bleeding.

Once activated, plasma kallikrein binds to collagen and therebyinterferes with collagen-mediated activation of platelets mediated byGPVI receptors (Liu et al. (Nat Med., 2011, 17, 206-210)). As discussedabove, plasma kallikrein inhibitors reduce plasma prekallikreinactivation by inhibiting plasma kallikrein-mediated activation of factorXII and thereby reducing the positive feedback amplification of thekallikrein system by the contact activation system.

Therefore, inhibition of plasma kallikrein reduces the binding of plasmakallikrein to collagen, thus reducing the interference of plasmakallikrein in the cessation of bleeding. Therefore plasma kallikreininhibitors would be useful in the treatment of treating cerebralhaemorrhage and bleeding from post operative surgery. For example, Liuet al. (Nat Med., 2011, 17, 206-210) demonstrated that systemicadministration of a small molecule PK inhibitor, ASP-440, reducedhematoma expansion in rats. Cerebral hematoma may occur followingintracerebral haemorrhage and is caused by bleeding from blood vesselsinto the surrounding brain tissue as a result of vascular injury.Bleeding in the cerebral haemorrhage model reported by Liu et al. wasinduced by surgical intervention involving an incision in the brainparenchyma that damaged blood vessels. These data demonstrate thatplasma kallikrein inhibition reduced bleeding and hematoma volume frompost operative surgery. Bjorkqvist et al. (Thrombosis and Haemostasis,2013, 110, 399-407) demonstrated that aprotinin (a protein that inhibitsserine proteases including plasma kallikrein) may be used to decreasepostoperative bleeding.

Other complications of diabetes such as cerebral haemorrhage,nephropathy, cardiomyopathy and neuropathy, all of which haveassociations with plasma kallikrein may also be considered as targetsfor a plasma kallikrein inhibitor.

Synthetic and small molecule plasma kallikrein inhibitors have beendescribed previously, for example by Garrett et al. (“Peptide aldehyde .. . ” J. Peptide Res. 52, p 62-71 (1998)), T. Griesbacher et al.(“Involvement of tissue kallikrein but not plasma kallikrein in thedevelopment of symptoms mediated by endogenous kinins in acutepancreatitis in rats” British Journal of Pharmacology 137, p 692-700(2002)), Evans (“Selective dipeptide inhibitors of kallikrein”WO003/076458), Szelke et al. (“Kininogenase inhibitors” WO92/04371), D.M. Evans et al. (Immunolpharmacology, 32, p 115-116 (1996)), Szelke etal. (“Kininogen inhibitors” WO95/07921), Antonsson et al. (“New peptidesderivatives” WO94/29335), J. Corte et al. (“Six membered heterocyclesuseful as serine protease inhibitors” WO2005/123680), J. Stürzbecher etal. (Brazilian J. Med. Biol. Res 27, p 1929-34 (1994)), Kettner et al.(U.S. Pat. No. 5,187,157), N. Teno et al. (Chem. Pharm. Bull. 41, p1079-1090 (1993)), W. B. Young et al. (“Small molecule inhibitors ofplasma kallikrein” Bioorg. Med. Chem. Letts. 16, p 2034-2036 (2006)),Okada et al. (“Development of potent and selective plasmin and plasmakallikrein inhibitors and studies on the structure-activityrelationship” Chem. Pharm. Bull. 48, p 1964-72 (2000)), Steinmetzer etal. (“Trypsin-like serine protease inhibitors and their preparation anduse” WO08/049595), Zhang et al. (“Discovery of highly potent smallmolecule kallikrein inhibitors” Medicinal Chemistry 2, p 545-553(2006)), Sinha et al. (“Inhibitors of plasma kallikrein” WO08/016883),Shigenaga et al. (“Plasma Kallikrein Inhibitors” WO2011/118672), andKolte et al. (“Biochemical characterization of a novel high-affinity andspecific kallikrein inhibitor”, British Journal of Pharmacology (2011),162(7), 1639-1649). Also, Steinmetzer et al. (“Serine proteaseinhibitors” WO2012/004678) describes cyclized peptide analogs which areinhibitors of human plasmin and plasma kallikrein.

To date, no small molecule synthetic plasma kallikrein inhibitor hasbeen approved for medical use. The molecules described in the known artsuffer from limitations such as poor selectivity over related enzymessuch as KLK1, thrombin and other serine proteases, and poor oralavailability. The large protein plasma kallikrein inhibitors presentrisks of anaphylactic reactions, as has been reported for Ecallantide.Thus there remains a need for compounds that selectively inhibit plasmakallikrein, that do not induce anaphylaxis and that are orallyavailable. Furthermore, the vast majority of molecules in the known artfeature a highly polar and ionisable guanidine or amidine functionality.It is well known that such functionalities may be limiting to gutpermeability and therefore to oral availability. For example, it hasbeen reported by Tamie J. Chilcote and Sukanto Sinha (“ASP-634: An OralDrug Candidate for Diabetic MacularEdema”, ARVO 2012 May 6-May 9, 2012,Fort Lauderdale, Fla., Presentation 2240) that ASP-440, a benzamidine,suffers from poor oral availability. It is further reported thatabsorption may be improved by creating a prodrug such as ASP-634.However, it is well known that prodrugs can suffer from severaldrawbacks, for example, poor chemical stability and potential toxicityfrom the inert carrier or from unexpected metabolites. In anotherreport, indole amides are claimed as compounds that might overcomeproblems associated with drugs possessing poor or inadequate ADME-toxand physicochemical properties although no inhibition against plasmakallikrein is presented or claimed (Griffioen et al, “Indole amidederivatives and related compounds for use in the treatment ofneurodegenerative diseases”, WO2010, 142801).

BioCryst Pharmaceuticals Inc. have reported the discovery of the orallyavailable plasma kallikrein inhibitor BCX4161 (“BCX4161, An OralKallikrein Inhibitor: Safety and Pharmacokinetic Results Of a Phase 1Study In Healthy Volunteers”, Journal of Allergy and ClinicalImmunology, Volume 133, Issue 2, Supplement, February 2014, page AB39and “A Simple, Sensitive and Selective Fluorogenic Assay to MonitorPlasma Kallikrein Inhibitory Activity of BCX4161 in Activated Plasma”,Journal of Allergy and Clinical Immunology, Volume 133, Issue 2,Supplement February 2014, page AB40). However, human doses arerelatively large, currently being tested in proof of concept studies atdoses of 400 mg three times daily.

There are only few reports of plasma kallikrein inhibitors that do notfeature guanidine or amidine functionalities. One example is Brandl etal. (“N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides asinhibitors of plasma kallikrein” WO2012/017020), which describescompounds that feature an aminopyridine functionality. Oral efficacy ina rat model is demonstrated at relatively high doses of 30 mg/kg and 100mg/kg but the pharmacokinetic profile is not reported. Thus it is notyet known whether such compounds will provide sufficient oralavailability or efficacy for progression to the clinic. Other examplesare Brandl et al. (“Aminopyridine derivatives as plasma kallikreininhibitors” WO2013/111107) and Flohr et al. (“5-memberedheteroarylcarboxamide derivatives as plasma kallikrein inhibitors”WO2013/111108). However, neither of these documents report any in vivodata and therefore it is not yet known whether such compounds willprovide sufficient oral availability or efficacy for progression to theclinic. Another example is Allan et al. “Benzylamine derivatives”WO2014/108679.

Therefore there remains a need to develop new plasma kallikreininhibitors that will have utility to treat a wide range of disorders, inparticular to reduce retinal vascular permeability associated withdiabetic retinopathy and diabetic macular edema. Preferred compoundswill possess a good pharmacokinetic profile and in particular will besuitable as drugs for oral delivery.

SUMMARY OF THE INVENTION

The present invention relates to a series of heterocyclic derivativesthat are inhibitors of plasma kallikrein. These compounds demonstrategood selectivity for plasma kallikrein and are potentially useful in thetreatment of impaired visual acuity, diabetic retinopathy, macularedema, hereditary angioedema, diabetes, pancreatitis, cerebralhaemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory boweldisease, arthritis, inflammation, septic shock, hypotension, cancer,adult respiratory distress syndrome, disseminated intravascularcoagulation, blood coagulation during cardiopulmonary bypass surgery andbleeding from post operative surgery. The invention further relates topharmaceutical compositions of the inhibitors, to the use of thecompositions as therapeutic agents, and to methods of treatment usingthese compositions.

The present invention provides compounds closely related to, or fallingwithin the scope of, but not specifically disclosed in, our co-pendingapplication PCT/GB2015/053615 (WO2016/083820).

In a first aspect, the present invention provides compounds selectedfrom the group consisting of:

-   N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-fluoro-5-methoxypyridazin-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-(methoxymethyl)-N-[(5-methoxypyridazin-3-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-(methoxymethyl)-N-[(6-methoxypyrimidin-4-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-amino-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;-   3-(dimethylamino)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-cyano-2-methoxypyridin-4-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-cyano-3-fluoro-2-methoxypyridin-4-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-(methoxymethyl)-N-[(4-methoxypyrimidin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-cyano-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-cyanopyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[3-(difluoromethyl)-4-methoxypyridin-2-yl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-chloro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-chloro-3-cyanopyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-chloro-3-fluoropyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-chloro-3-fluoropyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-fluoro-5-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-methoxy-5-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-cyano-5-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-methoxy-3-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-cyano-6-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[6-(difluoromethyl)-3-fluoro-4-methoxypyridin-2-yl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-(difluoromethyl)-3-fluoro-4-methoxypyridin-2-yl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3,5-difluoropyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-fluoro-6-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-fluoro-4-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-chloro-4-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyrid    in-2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;-   N-[(5-methoxy-1-methyl    pyrazol-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-chloro-5-methoxy-1-methyl    pyrazol-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-methoxy-1,4-dimethyl    pyrazol-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-chloro-1-methyl    pyrazol-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-amino-N-[(2,6-difluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(2,6-difluoro-3,5-dimethoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-methoxy-2-methyl    phenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(6-carbamoyl-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-amino-N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(dimethylamino)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-amino-N-[(2-cyano-5-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-5-methoxyphenyl)methyl]-3-(dimethylamino)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-amino-N-{[5-methoxy-2-(trifluoromethyl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-amino-N-{[2-(difluoromethyl)-5-methoxyphenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-fluoro-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(2,6-difluoro-3-methoxyphenyl)methyl]-3-(dimethyl    amino)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({5-[(2-oxopyridin-1-yl)methyl]pyridin-2-yl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({6-[(2-oxopyridin-1-yl)methyl]pyridin-3-yl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;-   N-[(2-cyano-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({5-[(2-oxopyridin-1-yl)methyl]pyridin-2-yl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({6-[(2-oxopyridin-1-yl)methyl]pyridin-3-yl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-5-methoxyphenyl)methyl]-1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopiperidin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(4-methyl    pyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(4-methyl    pyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(4-methyl    pyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;-   3-amino-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-amino-N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-amino-N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-(dimethylamino)-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-(dimethylamino)-N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-(dimethylamino)-N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-amino-N-{[5-chloro-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-chloro-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-chloro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-{[2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}pyrazole-4-carboxamide;-   3-(methoxymethyl)-N-{[2-methyl-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-6-fluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;-   1-{[2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;-   1-{[6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]methyl}-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;-   1-{[2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}-N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;-   1-{[6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]methyl}-N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;    -   and pharmaceutically acceptable salts and solvates thereof.

In a further aspect of the present invention, also provided is acompound selected from the group consisting of:

-   N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-(methoxymethyl)-N-[(4-methoxypyrimidin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-chloro-3-cyanopyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-chloro-3-fluoropyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3,5-difluoropyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-fluoro-6-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-fluoro-4-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-chloro-4-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-chloro-1-methylpyrazol-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;    -   and pharmaceutically acceptable salts and solvates thereof.

In another aspect of the present invention, also provided is a compoundselected from the group consisting of:

-   N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-amino-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;-   N-[(3-cyano-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-cyanopyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[3-(difluoromethyl)-4-methoxypyridin-2-yl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-methoxy-5-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-methoxy-3-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-cyano-6-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[6-(difluoromethyl)-3-fluoro-4-methoxypyridin-2-yl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyrid    in-2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;-   3-amino-N-[(2,6-difluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-methoxy-2-methylphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(6-carbamoyl-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-amino-N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(dimethylamino)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-amino-N-[(2-cyano-5-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-fluoro-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({5-[(2-oxopyridin-1-yl)methyl]pyridin-2-yl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({6-[(2-oxopyridin-1-yl)methyl]pyridin-3-yl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;-   N-[(2-cyano-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({5-[(2-oxopyridin-1-yl)methyl]pyridin-2-yl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({6-[(2-oxopyridin-1-yl)methyl]pyridin-3-yl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-5-methoxyphenyl)methyl]-1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;-   N-[(2-cyano-6-fluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;    -   and pharmaceutically acceptable salts and solvates thereof.

In a further aspect of the present invention, also provided is acompound selected from the group consisting of:

-   N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({5-[(2-oxopyridin-1-yl)methyl]pyridin-2-yl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({6-[(2-oxopyridin-1-yl)methyl]pyridin-3-yl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({5-[(2-oxopyridin-1-yl)methyl]pyridin-2-yl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({6-[(2-oxopyridin-1-yl)methyl]pyridin-3-yl}methyl)pyrazole-4-carboxamide;    -   and pharmaceutically acceptable salts and solvates thereof.

In a further aspect of the present invention, also provided is acompound selected from the group consisting of:

-   N-[(3-fluoro-4-methoxypyrid    in-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(4-methyl    pyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-(methoxymethyl)-N-[(6-methoxypyrimidin-4-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-amino-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;-   3-(dimethylamino)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-cyano-2-methoxypyridin-4-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-(methoxymethyl)-N-[(4-methoxypyrimidin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-cyanopyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-chloro-3-cyanopyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-chloro-3-fluoropyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-methoxy-5-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-methoxy-3-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3,5-difluoropyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-fluoro-6-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-fluoro-4-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-chloro-4-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyrid    in-2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;-   N-[(5-methoxy-1-methyl    pyrazol-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-chloro-1-methyl    pyrazol-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-amino-N-[(2,6-difluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-methoxy-2-methylphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(6-carbamoyl-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-amino-N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(dimethylamino)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-fluoro-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({5-[(2-oxopyridin-1-yl)methyl]pyridin-2-yl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({6-[(2-oxopyridin-1-yl)methyl]pyridin-3-yl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(4-methyl    pyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;-   3-amino-N-{[5-chloro-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-chloro-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-chloro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-{[2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   1-{[2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;    and-   pharmaceutically acceptable salts and solvates thereof.

In a further aspect of the present invention, also provided is acompound selected from the group consisting of:

-   3-amino-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;-   3-(dimethylamino)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-cyano-2-methoxypyridin-4-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-chloro-3-cyanopyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-chloro-3-fluoropyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-methoxy-3-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-fluoro-4-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-chloro-4-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyrid    in-2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;-   3-amino-N-[(2,6-difluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-methoxy-2-methylphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(6-carbamoyl-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-amino-N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(dimethylamino)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-fluoro-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({5-[(2-oxopyridin-1-yl)methyl]pyridin-2-yl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({6-[(2-oxopyridin-1-yl)methyl]pyridin-3-yl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;-   3-amino-N-{[5-chloro-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-chloro-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-chloro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-{[2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   1-{[2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;    and-   pharmaceutically acceptable salts and solvates thereof.

In a further aspect of the present invention, also provided is acompound selected from the group consisting of:

-   3-amino-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;-   N-[(4-methoxy-3-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyrid    in-2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;-   3-amino-N-[(2,6-difluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(6-carbamoyl-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-amino-N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(dimethylamino)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({6-[(2-oxopyridin-1-yl)methyl]pyridin-3-yl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(4-methyl    pyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(4-methyl    pyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;-   3-amino-N-{[5-chloro-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-chloro-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   1-{[2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;    and-   pharmaceutically acceptable salts and solvates thereof.

In a further aspect of the present invention, also provided is acompound selected from the group consisting of:

-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;-   1-{[2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;-   1-{[6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]methyl}-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;-   1-{[2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}-N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;-   1-{[6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]methyl}-N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;    -   and pharmaceutically acceptable salts and solvates thereof.-   In a yet further aspect of the present invention, also provided is a    compound selected from the group consisting of:-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   1-{[2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;-   1-{[6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]methyl}-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;-   1-{[2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}-N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide    and pharmaceutically acceptable salts and solvates thereof.-   In a preferred aspect of the present invention, also provided is a    compound that is    N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;    or a pharmaceutically acceptable salt or solvate thereof.

In a preferred aspect of the present invention, also provided is acompound that isN-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;or a pharmaceutically acceptable salt or solvate thereof.

In a preferred aspect of the present invention, also provided is acompound that isN-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;or a pharmaceutically acceptable salt or solvate thereof.

In a preferred aspect of the present invention, also provided is acompound that isN-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;or a pharmaceutically acceptable salt or solvate thereof.

In a preferred aspect of the present invention, also provided is acompound that is1-{[2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;or a pharmaceutically acceptable salt or solvate thereof.

In a preferred aspect of the present invention, also provided is acompound that is1-{[6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]methyl}-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;or a pharmaceutically acceptable salt or solvate thereof.

In a preferred aspect of the invention, also provided is a compound thatisN-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;or a pharmaceutically acceptable salt or solvate thereof.

In a preferred aspect of the invention, also provided is a compound thatisN-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;or a pharmaceutically acceptable salt or solvate thereof.

In a preferred aspect of the invention, also provided is a compound thatis1-{[2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}-N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;or a pharmaceutically acceptable salt of solvate thereof.

In a preferred aspect of the invention, also provided is a compound thatisN-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;or a pharmaceutically acceptable salt or solvate thereof.

In a preferred aspect of the invention, also provided is a compound thatisN-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({5-[(2-oxopyridin-1-yl)methyl]pyridin-2-yl}methyl)pyrazole-4-carboxamide;or a pharmaceutically acceptable salt or solvate thereof.

In a preferred aspect of the invention, also provided is a compound thatisN-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({6-[(2-oxopyridin-1-yl)methyl]pyridin-3-yl}methyl)pyrazole-4-carboxamide;or a pharmaceutically acceptable salt or solvate thereof.

In a yet further aspect of the present invention, also provided is acompound selected from the group consisting of:

-   N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-fluoro-5-methoxypyridazin-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-(methoxymethyl)-N-[(5-methoxypyridazin-3-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-(methoxymethyl)-N-[(6-methoxypyrimidin-4-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-cyano-2-methoxypyridin-4-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-cyano-3-fluoro-2-methoxypyridin-4-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-(methoxymethyl)-N-[(4-methoxypyrimidin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-cyano-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-cyanopyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[3-(difluoromethyl)-4-methoxypyridin-2-yl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-chloro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-chloro-3-cyanopyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-chloro-3-fluoropyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-chloro-3-fluoropyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-fluoro-5-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-methoxy-5-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-cyano-5-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-methoxy-3-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-cyano-6-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[6-(difluoromethyl)-3-fluoro-4-methoxypyridin-2-yl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-(difluoromethyl)-3-fluoro-4-methoxypyridin-2-yl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3,5-difluoropyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-fluoro-6-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-fluoro-4-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(3-chloro-4-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyrid    in-2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;-   N-[(5-methoxy-1-methyl    pyrazol-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-chloro-5-methoxy-1-methyl    pyrazol-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-methoxy-1,4-dimethyl    pyrazol-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(4-chloro-1-methyl    pyrazol-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(2,6-difluoro-3,5-dimethoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(5-methoxy-2-methylphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(6-carbamoyl-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-fluoro-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({5-[(2-oxopyridin-1-yl)methyl]pyridin-2-yl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({6-[(2-oxopyridin-1-yl)methyl]pyridin-3-yl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;-   N-[(2-cyano-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({5-[(2-oxopyridin-1-yl)methyl]pyridin-2-yl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({6-[(2-oxopyridin-1-yl)methyl]pyridin-3-yl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-5-methoxyphenyl)methyl]-1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopiperidin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(4-methyl    pyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(4-methyl    pyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-chloro-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-chloro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-{[2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}pyrazole-4-carboxamide;-   3-(methoxymethyl)-N-{[2-methyl-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-[(2-cyano-6-fluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   1-{[2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;-   1-{[6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]methyl}-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;-   1-{[2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}-N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;-   1-{[6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]methyl}-N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;    -   and pharmaceutically acceptable salts and solvates thereof.

In a yet further aspect of the present invention, also provided is acompound selected from the group consisting of:

-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(4-methyl    pyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;-   3-amino-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-amino-N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-(dimethylamino)-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   3-(dimethylamino)-N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;-   N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;-   N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;-   1-{[2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;-   1-{[6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]methyl}-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;-   1-{[2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}-N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;-   1-{[6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]methyl}-N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;    -   and pharmaceutically acceptable salts and solvates thereof.

In another aspect the present invention provides a prodrug of a compoundof the invention, or a pharmaceutically acceptable salt thereof.

In yet another aspect the present invention provides an N-oxide of acompound of the invention, or a prodrug or pharmaceutically acceptablesalt thereof.

It will be understood that certain compounds of the present inventionmay exist in solvated, for example hydrated, as well as unsolvatedforms. It is to be understood that the present invention encompasses allsuch solvated forms.

Therapeutic Applications

As previously mentioned, the compounds of the present invention arepotent and selective inhibitors of plasma kallikrein. They are thereforeuseful in the treatment of disease conditions for which over-activity ofplasma kallikrein is a causative factor.

Accordingly, the present invention provides a compound of the inventionfor use in medicine.

The present invention also provides for the use of a compound of theinvention in the manufacture of a medicament for the treatment orprevention of a disease or condition in which plasma kallikrein activityis implicated.

The present invention also provides a compound of the invention for usein the treatment or prevention of a disease or condition in which plasmakallikrein activity is implicated.

The present invention also provides a method of treatment of a diseaseor condition in which plasma kallikrein activity is implicatedcomprising administration to a subject in need thereof a therapeuticallyeffective amount of a compound of the invention.

In one aspect, the disease or condition in which plasma kallikreinactivity is implicated is selected from impaired visual acuity, diabeticretinopathy, diabetic macular edema, hereditary angioedema, diabetes,pancreatitis, cerebral haemorrhage, nephropathy, cardiomyopathy,neuropathy, inflammatory bowel disease, arthritis, inflammation, septicshock, hypotension, cancer, adult respiratory distress syndrome,disseminated intravascular coagulation, blood coagulation duringcardiopulmonary bypass surgery and bleeding from post operative surgery.

In a preferred aspect, the disease or condition in which plasmakallikrein activity is implicated is retinal vascular permeabilityassociated with diabetic retinopathy and diabetic macular edema.

In an alternative preferred aspect, the disease or condition in whichplasma kallikrein activity is implicated is hereditary angioedema.

In an alternative preferred aspect, the disease or condition in whichplasma kallikrein activity is implicated is diabetic macular edema.

In another aspect, the disease or condition in which plasma kallikreinactivity is implicated is retinal vein occlusion.

Combination Therapy

The compounds of the present invention may be administered incombination with other therapeutic agents. Suitable combinationtherapies include a compound of the invention combined with one or moreagents selected from agents that inhibit platelet-derived growth factor(PDGF), endothelial growth factor (VEGF), integrin alpha5beta1,steroids, other agents that inhibit plasma kallikrein and otherinhibitors of inflammation. Specific examples of therapeutic agents thatmay be combined with the compounds of the present invention includethose disclosed in EP2281885A and by S. Patel in Retina, 2009 June; 29(6Suppl):S45-8.

When combination therapy is employed, the compounds of the presentinvention and said combination agents may exist in the same or differentpharmaceutical compositions, and may be administered separately,sequentially or simultaneously.

In another aspect, the compounds of the present invention may beadministered in combination with laser treatment of the retina. Thecombination of laser therapy with intravitreal injection of an inhibitorof VEGF for the treatment of diabetic macular edema is known (Elman M,Aiello L, Beck R, et al. “Randomized trial evaluating ranibizumab plusprompt or deferred laser or triamcinolone plus prompt laser for diabeticmacular edema”. Ophthalmology. 27 Apr. 2010).

Definitions

The term “alkyl” includes saturated hydrocarbon residues including:

-   -   linear groups up to 10 carbon atoms (C₁-C₁₀), or of up to 6        carbon atoms (C₁-C₆), or of up to 4 carbon atoms (C₁-C₄).        Examples of such alkyl groups include, but are not limited, to        C₁-methyl, C₂-ethyl, C₃-propyl and C₄-n-butyl.    -   branched groups of between 3 and 10 carbon atoms (C₃-C₁₀), or of        up to 7 carbon atoms (C₃-C₇), or of up to 4 carbon atoms        (C₃-C₄). Examples of such alkyl groups include, but are not        limited to, C₃-iso-propyl, C₄-sec-butyl, C₄-iso-butyl,        C₄-tert-butyl and C₅-neo-pentyl.

each optionally substituted as stated above.

Cycloalkyl is a monocyclic saturated hydrocarbon of between 3 and 7carbon atoms, or between 3 and 6 carbon atoms, or between 3 and 5 carbonatoms. Optionally, cycloalkyl may be substituted with a substituentselected from alkyl, alkoxy and NR12R13; wherein R12 and R13 areindependently selected from H and alkyl or R12 and R13 together with thenitrogen to which they are attached form a 4-, 5-, 6- or 7-memberedheterocylic ring which may be saturated or unsaturated with 1 or 2double bonds and which may be optionally mono- or di-substituted withsubstituents selected from oxo, alkyl, alkoxy, OH, F and CF₃. Cycloalkylgroups may contain from 3 to 7 carbon atoms, or from 3 to 6 carbonatoms, or from 3 to 5 carbon atoms, or from 3 to 4 carbon atoms.Examples of suitable monocyclic cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term “alkoxy” includes O-linked hydrocarbon residues including:

-   -   linear groups of between 1 and 6 carbon atoms (C₁-C₆), or of        between 1 and 4 carbon atoms (C₁-C₄). Examples of such alkoxy        groups include, but are not limited to, C₁-methoxy, C₂-ethoxy,        C₃-n-propoxy and C₄-n-butoxy.    -   branched groups of between 3 and 6 carbon atoms (C₃-C₆) or of        between 3 and 4 carbon atoms (C₃-C₄). Examples of such alkoxy        groups include, but are not limited to, C₃-iso-propoxy, and        C₄-sec-butoxy and tert-butoxy.

each optionally substituted as stated above.

Unless otherwise stated, halo is selected from Cl, F, Br and I.

Aryl is as defined above. Typically, aryl will be optionally substitutedwith 1, 2 or 3 substituents.

Optional substituents are selected from those stated above. Examples ofsuitable aryl groups include phenyl and naphthyl (each optionallysubstituted as stated above). Preferably aryl is selected from phenyl,substituted phenyl (wherein said substituents are selected from thosestated above) and naphthyl.

Heteroaryl is as defined above. Typically, heteroaryl will be optionallysubstituted with 1, 2 or 3 substituents. Optional substituents areselected from those stated above. Examples of suitable heteroaryl groupsinclude thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolyl, benzimidazolyl, benzotriazolyl, quinolinyl andisoquinolinyl (optionally substituted as stated above).

The term “N-linked”, such as in “N-linked pyrrolidinyl”, means that theheterocycloalkyl group is joined to the remainder of the molecule via aring nitrogen atom.

The term “O-linked”, such as in “O-linked hydrocarbon residue”, meansthat the hydrocarbon residue is joined to the remainder of the moleculevia an oxygen atom.

In groups such as —(CH₂)₁₋₃-aryl, “-” denotes the point of attachment ofthe substituent group to the remainder of the molecule.

“Pharmaceutically acceptable salt” means a physiologically ortoxicologically tolerable salt and includes, when appropriate,pharmaceutically acceptable base addition salts and pharmaceuticallyacceptable acid addition salts. For example (i) where a compound of theinvention contains one or more acidic groups, for example carboxygroups, pharmaceutically acceptable base addition salts that can beformed include sodium, potassium, calcium, magnesium and ammonium salts,or salts with organic amines, such as, diethylamine, N-methyl-glucamine,diethanolamine or amino acids (e.g. lysine) and the like; (ii) where acompound of the invention contains a basic group, such as an aminogroup, pharmaceutically acceptable acid addition salts that can beformed include hydrochlorides, hydrobromides, sulfates, phosphates,acetates, citrates, lactates, tartrates, mesylates, succinates,oxalates, phosphates, esylates, tosylates, benzenesulfonates,naphthalenedisulphonates, maleates, adipates, fumarates, hippurates,camphorates, xinafoates, p-acetamidobenzoates, dihydroxybenzoates,hydroxynaphthoates, succinates, ascorbates, oleates, bisulfates and thelike.

Hemisalts of acids and bases can also be formed, for example,hemisulfate and hemicalcium salts.

For a review of suitable salts, see “Handbook of Pharmaceutical Salts:Properties, Selection and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

“Prodrug” refers to a compound which is convertible in vivo by metabolicmeans (e.g. by hydrolysis, reduction or oxidation) to a compound of theinvention. Suitable groups for forming prodrugs are described in ‘ThePractice of Medicinal Chemistry, 2^(nd) Ed. pp 561-585 (2003) and in F.J. Leinweber, Drug Metab. Res., 1987, 18, 379.

The compounds of the invention can exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and a stoichiometric amount ofone or more pharmaceutically acceptable solvent molecules, for example,ethanol. The term ‘hydrate’ is employed when the solvent is water.

Where compounds of the invention exist in one or more geometrical,optical, enantiomeric, diastereomeric and tautomeric forms, includingbut not limited to cis- and trans-forms, E- and Z-forms, R-, S- andmeso-forms, keto-, and enol-forms, unless otherwise stated a referenceto a particular compound includes all such isomeric forms, includingracemic and other mixtures thereof. Where appropriate such isomers canbe separated from their mixtures by the application or adaptation ofknown methods (e.g. chromatographic techniques and recrystallisationtechniques). Where appropriate such isomers can be prepared by theapplication or adaptation of known methods (e.g. asymmetric synthesis).

A reference to a particular compound also includes all isotopicvariants.

In the context of the present invention, references herein to“treatment” include references to curative and palliative treatment.

General Methods

The compounds of the invention should be assessed for theirbiopharmaceutical properties, such as solubility and solution stability(across pH), permeability, etc., in order to select the most appropriatedosage form and route of administration for treatment of the proposedindication. They may be administered alone or in combination with one ormore other compounds of the invention or in combination with one or moreother drugs (or as any combination thereof). Generally, they will beadministered as a formulation in association with one or morepharmaceutically acceptable excipients.

The term ‘excipient’ is used herein to describe any ingredient otherthan the compound(s) of the invention which may impart either afunctional (i.e., drug release rate controlling) and/or a non-functional(i.e., processing aid or diluent) characteristic to the formulations.The choice of excipient will to a large extent depend on factors such asthe particular mode of administration, the effect of the excipient onsolubility and stability, and the nature of the dosage form.

Compounds of the invention intended for pharmaceutical use may beadministered as a solid or liquid, such as a tablet, capsule orsolution. Pharmaceutical compositions suitable for the delivery ofcompounds of the present invention and methods for their preparationwill be readily apparent to those skilled in the art. Such compositionsand methods for their preparation may be found, for example, inRemington's Pharmaceutical Sciences, 19th Edition (Mack PublishingCompany, 1995).

Accordingly, the present invention provides a pharmaceutical compositioncomprising a compound of the invention and a pharmaceutically acceptablecarrier, diluent or excipient.

For the treatment of conditions such as retinal vascular permeabilityassociated with diabetic retinopathy and diabetic macular edema, thecompounds of the invention may be administered in a form suitable forinjection into the ocular region of a patient, in particular, in a formsuitable for intra-vitreal injection. It is envisaged that formulationssuitable for such use will take the form of sterile solutions of acompound of the invention in a suitable aqueous vehicle. Thecompositions may be administered to the patient under the supervision ofthe attending physician.

The compounds of the invention may also be administered directly intothe blood stream, into subcutaneous tissue, into muscle, or into aninternal organ. Suitable means for parenteral administration includeintravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial and subcutaneous. Suitable devices forparenteral administration include needle (including microneedle)injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous or oily solutions. Wherethe solution is aqueous, excipients such as sugars (including but notrestricted to glucose, manitol, sorbitol, etc.), salts, carbohydratesand buffering agents (preferably to a pH of from 3 to 9), but, for someapplications, they may be more suitably formulated as a sterilenon-aqueous solution or as a dried form to be used in conjunction with asuitable vehicle such as sterile, pyrogen-free water.

Parenteral formulations may include implants derived from degradablepolymers such as polyesters (i.e., polylactic acid, polylactide,polylactide-co-glycolide, polycapro-lactone, polyhydroxybutyrate),polyorthoesters and polyanhydrides. These formulations may beadministered via surgical incision into the subcutaneous tissue,muscular tissue or directly into specific organs.

The preparation of parenteral formulations under sterile conditions, forexample, by lyophilisation, may readily be accomplished using standardpharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of the invention used in the preparation ofparenteral solutions may be increased by the use of appropriateformulation techniques, such as the incorporation of co-solvents and/orsolubility-enhancing agents such as surfactants, micelle structures andcyclodextrins.

In one embodiment, the compounds of the invention may be administeredorally. Oral administration may involve swallowing, so that the compoundenters the gastrointestinal tract, and/or buccal, lingual, or sublingualadministration by which the compound enters the blood stream directlyfrom the mouth.

Formulations suitable for oral administration include solid plugs, solidmicroparticulates, semi-solid and liquid (including multiple phases ordispersed systems) such as tablets; soft or hard capsules containingmulti- or nano-particulates, liquids, emulsions or powders; lozenges(including liquid-filled); chews; gels; fast dispersing dosage forms;films; ovules; sprays; and buccal/mucoadhesive patches.

Formulations suitable for oral administration may also be designed todeliver the compounds of the invention in an immediate release manner orin a rate-sustaining manner, wherein the release profile can be delayed,pulsed, controlled, sustained, or delayed and sustained or modified insuch a manner which optimises the therapeutic efficacy of the saidcompounds. Means to deliver compounds in a rate-sustaining manner areknown in the art and include slow release polymers that can beformulated with the said compounds to control their release.

Examples of rate-sustaining polymers include degradable andnon-degradable polymers that can be used to release the said compoundsby diffusion or a combination of diffusion and polymer erosion.

Examples of rate-sustaining polymers include hydroxypropylmethylcellulose, hydroxypropyl cellulose, methyl cellulose, ethylcellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, xanthum gum, polymethacrylates, polyethylene oxide andpolyethylene glycol.

Liquid (including multiple phases and dispersed systems) formulationsinclude emulsions, solutions, syrups and elixirs. Such formulations maybe presented as fillers in soft or hard capsules (made, for example,from gelatin or hydroxypropylmethylcellulose) and typically comprise acarrier, for example, water, ethanol, polyethylene glycol, propyleneglycol, methylcellulose, or a suitable oil, and one or more emulsifyingagents and/or suspending agents. Liquid formulations may also beprepared by the reconstitution of a solid, for example, from a sachet.

The compounds of the invention may also be used in fast-dissolving,fast-disintegrating dosage forms such as those described in Liang andChen, Expert Opinion in Therapeutic Patents, 2001, 11 (6), 981-986.

The formulation of tablets is discussed in Pharmaceutical Dosage Forms:Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, NewYork, 1980).

For administration to human patients, the total daily dose of thecompounds of the invention is typically in the range 0.1 mg and 10,000mg, or between 1 mg and 5000 mg, or between 10 mg and 1000 mg depending,of course, on the mode of administration. If administered byintra-vitreal injection a lower dose of between 0.0001 mg (0.1 μg) and0.2 mg (200 μg) per eye is envisaged, or between 0.0005 mg (0.5 μg) and0.05 mg (50 μg) per eye.

The total dose may be administered in single or divided doses and may,at the physician's discretion, fall outside of the typical range givenherein. These dosages are based on an average human subject having aweight of about 60 kg to 70 kg. The physician will readily be able todetermine doses for subjects whose weight falls outside this range, suchas infants and the elderly.

Synthetic Methods

The compounds of the present invention can be prepared according to theprocedures of the following schemes and examples, using appropriatematerials, and are further exemplified by the specific examples providedherein below. Moreover, by utilising the procedures described herein,one of ordinary skill in the art can readily prepare additionalcompounds that fall within the scope of the present invention claimedherein. The compounds illustrated in the examples are not, however, tobe construed as forming the only genus that is considered as theinvention. The examples further illustrate details for the preparationof the compounds of the present invention. Those skilled in the art willreadily understand that known variations of the conditions and processesof the following preparative procedures can be used to prepare thesecompounds.

The compounds of the invention may be isolated in the form of theirpharmaceutically acceptable salts, such as those described previouslyherein above.

It may be necessary to protect reactive functional groups (e.g. hydroxy,amino, thio or carboxy) in intermediates used in the preparation ofcompounds of the invention to avoid their unwanted participation in areaction leading to the formation of the compounds. Conventionalprotecting groups, for example those described by T. W. Greene and P. G.M. Wuts in “Protective groups in organic chemistry” John Wiley and Sons,4^(th) Edition, 2006, may be used. For example, a common aminoprotecting group suitable for use herein is tert-butoxy carbonyl (Boc),which is readily removed by treatment with an acid such astrifluoroacetic acid or hydrogen chloride in an organic solvent such asdichloromethane. Alternatively the amino protecting group may be abenzyloxycarbonyl (Z) group which can be removed by hydrogenation with apalladium catalyst under a hydrogen atmosphere or9-fluorenylmethyloxycarbonyl (Fmoc) group which can be removed bysolutions of secondary organic amines such as diethylamine or piperidinein an organic solvent. Carboxyl groups are typically protected as esterssuch as methyl, ethyl, benzyl or tert-butyl which can all be removed byhydrolysis in the presence of bases such as lithium or sodium hydroxide.Benzyl protecting groups can also be removed by hydrogenation with apalladium catalyst under a hydrogen atmosphere whilst tert-butyl groupscan also be removed by trifluoroacetic acid. Alternatively atrichloroethyl ester protecting group is removed with zinc in aceticacid. A common hydroxy protecting group suitable for use herein is amethyl ether, deprotection conditions comprise refluxing in 48% aqueousHBr for 1-24 hours, or by stirring with borane tribromide indichloromethane for 1-24 hours. Alternatively where a hydroxy group isprotected as a benzyl ether, deprotection conditions comprisehydrogenation with a palladium catalyst under a hydrogen atmosphere.

Examples of synthetic methods that may be used to prepare4-carboxyimidazoles are described in EP 1426364 A1(“Imidazole-derivatives as factor Xa inhibitors”, p 27-28).

The compounds according to general formula I below can be prepared usingconventional synthetic methods for example but not limited to, the routeoutlined in Scheme 1.

Compounds of formula (I) are defined as follows:

wherein

B is phenyl substituted with 1 to 4 substituents selected fromalkyl^(b), alkoxy, OH, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9,OCF₃, and CF₃;

or B is selected from benzothiophenyl, benzofuranyl, benzomorpholinyland a 5 or 6 membered heterocyclic ring containing one or twoheteroatoms selected from N, O and S; wherein said 5 or 6 memberedheterocyclic ring may be aromatic or non-aromatic; and wherein saidbenzothiophenyl, said benzofuranyl, said benzomorpholinyl or said 5 or 6membered heterocyclic ring is substituted with 1 to 3 substituentsselected from alkyl^(b), alkoxy, OH, oxo, halo, CN, heteroaryl, COOR8,NHCOR8, CONR8R9, OCF₃ and CF₃;

W is C and X, Y and Z are independently selected from C, N, O and S,such that the ring containing W, X, Y and Z is a five membered aromaticheterocycle;

R5 and R6 are independently absent or independently selected from H,alkyl, cycloalkyl, alkoxy, halo, OH, aryl, heteroaryl, N-linkedpyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl, N-linkedpiperazinyl, —NR8R9, CN, COOR8, CONR8R9, —NR8COR9 and CF₃; wherein atleast one of R5 and R6 is present and is not H;

R7 is H;

A is selected from aryl and heteroaryl; wherein aryl is substituted with1, 2 or 3 substituents independently selected from alkyl, alkoxy,methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl,—(CH₂)₀₋₃—O-heteroaryl, aryl^(b), —O-aryl^(b), —(CH₂)₁₋₃-aryl^(b),—(CH₂)₁₋₃-heteroaryl, —COOR10, —CONR10R11, —(CH₂)₀₋₃—NR10R11, OCF₃ andCF₃; and heteroaryl is substituted with 1, 2 or 3 substituentsindependently selected from alkyl, alkoxy, OH, OCF₃, halo, CN, aryl,—(CH₂)₁₋₃-aryl, —(CH₂)₀₋₃—NR10R11, heteroaryl^(b), —COOR10, —CONR10R11and CF₃;

R8 and R9 are independently selected from H and alkyl;

alkyl is a linear saturated hydrocarbon having up to 10 carbon atoms(C₁-C₁₀) or a branched saturated hydrocarbon of between 3 and 10 carbonatoms (C₃-C₁₀); alkyl may optionally be substituted with 1 or 2substituents independently selected from (C₁-C₆)alkoxy, OH, CN, CF₃,COOR10, CONR10R11, fluoro and NR10R11;

alkyl^(b) is a linear saturated hydrocarbon having up to 6 carbon atomsor a branched saturated hydrocarbon of between 3 and 6 carbon atoms(C₃-6); alkyl^(b) may optionally be substituted with 1 or 2 substituentsindependently selected from (C₁-C₆)alkoxy, OH, CN, CF₃, COOR10,CONR1OR11 and fluoro;

cycloalkyl is a monocyclic saturated hydrocarbon of between 3 and 6carbon atoms;

alkoxy is a linear O-linked hydrocarbon of between 1 and 6 carbon atoms(C₁-C₆) or a branched O-linked hydrocarbon of between 3 and 6 carbonatoms (C₃-C₆); alkoxy may optionally be substituted with 1 or 2substituents independently selected from OH, CN, CF₃, COOR10, CONR1OR11,fluoro and NR10R11;

aryl is phenyl, biphenyl or naphthyl; aryl may be optionally substitutedwith 1, 2 or 3 substituents independently selected from alkyl, alkoxy,methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl,—(CH₂)₀₋₃—O-heteroaryl, aryl^(b), —O-aryl^(b), —(CH₂)₁₋₃-aryl^(b),—(CH₂)₁₋₃-heteroaryl, —COOR10, —CONR10R11, —(CH₂)₀₋₃—NR10R11, OCF₃ andCF₃;

aryl^(b) is phenyl, biphenyl or naphthyl, which may be optionallysubstituted with 1, 2 or 3 substituents independently selected fromalkyl, alkoxy, OH, halo, CN, —COOR10, —CONR1OR11, CF₃ and NR10R11;

heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring,containing, where possible, 1, 2, 3 or 4 ring members independentlyselected from N, NR8, S and O; heteroaryl may be optionally substitutedwith 1, 2 or 3 substituents independently selected from alkyl, alkoxy,OH, OCF₃, halo, CN, aryl, —(CH₂)₁₋₃-aryl, —(CH₂)₀₋₃—NR1OR11,heteroaryl^(b), —COOR10, —CONR1OR11 and CF₃;

heteroaryl^(b) is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromaticring, containing, where possible, 1, 2 or 3 ring members independentlyselected from N, NR8, S and O; wherein heteroaryl^(b) may be optionallysubstituted with 1, 2 or 3 substituents independently selected fromalkyl, alkoxy, OH, halo, CN, aryl, —(CH₂)₁₋₃-aryl, —COOR10, —CONR1OR11,CF₃ and NR1OR11; R10 and R11 are independently selected from H, alkyl,aryl^(b) and heteroaryl^(b) or R10 and R11 together with the nitrogenatom to which they are attached form a carbon-containing 4-, 5-, 6- or7-membered heterocylic ring, optionally containing an additionalheteroatom selected from N, S and O, which may be saturated orunsaturated with 1 or 2 double bonds and which may be optionally mono-or di-substituted with substituents selected from oxo, alkyl, alkoxy,OH, halo and CF₃;

and tautomers, isomers, stereoisomers (including enantiomers,diastereoisomers and racemic and scalemic mixtures thereof),pharmaceutically acceptable salts and solvates thereof.

In Scheme 1, the amine 2 is coupled to an acid 1 to give the compound 3.This coupling is typically carried out using standard couplingconditions such as hydroxybenzotriazole and a carbodiimide, such aswater soluble carbodiimide, in the presence of an organic base. Otherstandard coupling methods include the reaction of acids with amines inthe presence of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminiumhexafluorophosphate,2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V),benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoium hexaffluorophosphateor bromo-trispyrolidino-phosphoium hexafluorophosphate in the presenceof organic bases such as triethylamine, diisopropylethylamine orN-methylmorpholine. Alternatively the amide formation can take place viaan acid chloride in the presence of an organic base. Such acid chloridescan be formed by methods well known in the literature, for examplereaction of the acid with oxalyl chloride or thionyl chloride.Alternatively, the amide formation can take place via activation of thecarboxylic acid using carbonyl diimidazole.

Alternatively compounds of the invention can be prepared using the routeoutlined in Scheme 2a. The acid 4 can be coupled to an amine 2 usingsuitable coupling methods as previously described to give compound 5. Ina typical second step the nitrogen of the heterocyclic ring is alkylatedwith compound 6 to give compound 7. The alkylation can be carried out inthe presence of a base such as potassium carbonate, cesium carbonate,sodium carbonate or sodium hydride in which case the leaving group is ahalide or sulphonate. Alternatively the alkylation may be carried outusing an alcohol under Mitsunobu conditions in the presence oftriphenylphosphine.

In a variation of Scheme 2a compounds according to general formula I canbe prepared using the route outlined in Scheme 2b. Scheme 2b differsfrom Scheme 2a in that the moiety Y is equal to N therefore a protectinggroup strategy may be employed and the synthetic steps carried out in adifferent order. The pyrazole carboxylic acid, protected as an ester(PG) as described previously, compound 8, is alkylated with compound 6.The alkylation can be carried out in the presence of a base such aspotassium carbonate, cesium carbonate, sodium carbonate or sodiumhydride in which case the leaving group is a halide or sulphonate.Alternatively the alkylation may be carried out using an alcohol underMitsunobu conditions in the presence of triphenylphosphine. In this casethere are two possible nitrogens for the alkylation to occur attherefore there is the possibility of two regioisomers 9 and 10 beingformed. Compounds 9 and 10 may be separated at this stage or at asubsequent stage in the synthesis using separation methods well known tothose skilled in the art, for example by chromatography or by fractionalcrystallisation. The protecting group of compound 9 is removed byhydrolysis to give the corresponding acid 11 using standard methods asdescribed previously. Compound 11 can be coupled to an amine 2 usingsuitable coupling methods as previously described to give compound 12.

Alternatively compounds according to the invention can be prepared usingthe route outlined in Scheme 3. The pyrrole 17 can be formed in twosteps the first of which involves reaction of the sodium salt of analkyl ketoacetate 13, typically protected with a protecting group (PG)as described previously, with a chloroketone 14 in the presence of abase such as potassium carbonate to give compound 15 which in a typicalsecond step is reacted with the amine 16 in the presence of an acid suchas but not limited to sulphonic acid derivatives e.g. p-toluenesulphonicacid to yield compound 17 which in a typical third step is subsequentlyhydrolysed to the corresponding acid 18 using standard methods asdescribed previously. In a typical fourth step the acid 18 can becoupled to an amine 2 using suitable coupling methods as previouslydescribed to give compound 19.

The amine, compound 2 can be prepared using conventional syntheticmethods for example, but not limited to, the routes outlined in Scheme4. The nitrile of compound 20 is reduced by standard reducing agentsincluding but not limited to lithium aluminium hydride, sodiumborohydride, sodium borohydride and nickel chloride, sodium borohydrideand cobalt chloride, borane, and catalytic hydrogenation over a catalystsuch as palladium, platinum or Raney nickel. In some cases, for examplewhen the reducing agent is sodium borohydride or catalytic hydrogenationis employed, it is possible to carry out in situ protection of theresulting amino group, for example resulting in the carbamate 21, forexample tert-butoxy carbamate. This may be helpful to enable for examplepurification by chromatography of the intermediate compound 21. Theprotecting group is subsequently removed using standard conditions asdescribed previously to give compound 2.

EXAMPLES

The invention is illustrated by the following non-limiting examples inwhich the following abbreviations and definitions are used:

aq Aqueous solution DCM Dichloromethane DMF N,N-Dimethylformamide DMSODimethyl sulfoxide EtOAc Ethyl Acetate HATU2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)- 1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) hrs Hours HOBt Hydroxybenzotriazole LCMS Liquidchromatography mass spectrometry Me Methyl MeCN Acetonitrile MeOHMethanol Min Minutes MS Mass spectrum NMR Nuclear magnetic resonancespectrum - NMR spectra were recorded at a frequency of 400 MHz unlessotherwise indicated Pet. Ether Petroleum ether fraction boiling at60-80° C. Ph Phenyl SWFI Sterile water for injection rt room temperatureTHF Tetrahydrofuran TFA Trifluoroacetic acid

All reactions were carried out under an atmosphere of nitrogen unlessspecified otherwise.

¹H NMR spectra were recorded on a Bruker (400 MHz) spectrometer withreference to deuterium solvent and at rt.

Molecular ions were obtained using LCMS which was carried out using aChromolith Speedrod RP-18e column, 50×4.6 mm, with a linear gradient 10%to 90% 0.1% HCO₂H/MeCN into 0.1% HCO₂H/H₂O over 13 min, flow rate 1.5mL/min, or using Agilent, X-Select, acidic, 5-95% MeCN/water over 4 min.Data was collected using a Thermofinnigan Surveyor MSQ mass spectrometerwith electospray ionisation in conjunction with a ThermofinniganSurveyor LC system.

Where products were purified by flash chromatography, ‘silica’ refers tosilica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g.Merck silica gel 60), and an applied pressure of nitrogen up to 10 p.s.iaccelerated column elution. Reverse phase preparative HPLC purificationswere carried out using a Waters 2525 binary gradient pumping system atflow rates of typically 20 mL/min using a Waters 2996 photodiode arraydetector.

All solvents and commercial reagents were used as received.

Chemical names were generated using automated software such as theAutonom software provided as part of the ISIS Draw package from MDLInformation Systems or the Chemaxon software provided as a component ofMarvinSketch or as a component of the IDBS E-WorkBook.

A. 1-(4-Hydroxymethyl-benzyl)-1H-pyridin-2-one

4-(Chloromethyl)benzylalcohol (5.0 g, 31.93 mmol) was dissolved inacetone (150 mL). 2-hydroxypyridine (3.64 g, 38.3 mmol) and potassiumcarbonate (13.24 g, 95.78 mmol) were added and the reaction mixture wasstirred at 50° C. for 3 hrs after which time the solvent was removed invacuo and the residue taken up in chloroform (100 mL). This solution waswashed with water (30 mL), brine (30 mL), dried (Na₂SO₄) and evaporatedin vacuo. The residue was purified by flash chromatography (silica),eluent 3% MeOH/97% CHCl₃, to give a white solid identified as1-(4-hydroxymethyl-benzyl)-1H-pyridin-2-one (5.30 g, 24.62 mmol, 77%yield).

[M+Na]⁺=238

B1. 1-(4-Chloromethyl-benzyl)-1H-pyridin-2-one

1-(4-Hydroxymethyl-benzyl)-1H-pyridin-2-one (8.45 g, 39.3 mmol), dry DCM(80 mL) and triethylamine (7.66 ml, 55.0 mmol) were cooled in an icebath. Methanesulfonyl chloride (3.95 ml, 51.0 mmol) was added andstirred in ice bath for 15 min. The ice bath was removed and stirringcontinued at rt temperature overnight. The reaction mixture waspartitioned between DCM (100 mL) and saturated aqueous NH₄Cl solution(100 mL). The aqueous layer was extracted with further DCM (2×50 mL) andthe combined organics washed with brine (50 mL), dried over Na₂SO₄,filtered and concentrated to give1-(4-chloromethyl-benzyl)-1H-pyridin-2-one (8.65 g, 36.6 mmol, 93%yield) as a pale yellow solid.

[MH]⁺=234.1

B2. 1-(4-Bromomethyl-benzyl)-1H-pyridin-2-one

1-(4-Hydroxymethyl-benzyl)-1H-pyridin-2-one (2.30 g, 6.97 mmol) wasdissolved in DCM (250 mL). To this solution was added phosphoroustribromide (5.78 g, 21.37 mmol). The reaction mixture was stirred at rtfor 18 hrs and diluted with CHCl₃ (250 mL). The filtrate was washed withsat. NaHCO₃ (aq) (30 mL), water (30 mL), brine (30 mL), dried (Na₂SO₄)and evaporated in vacuo to give a white solid which was identified as1-(4-bromomethyl-benzyl)-1H-pyridin-2-one (2.90 g, 10.43 mmol, 98%).

[M+H]⁺=277.7

C. Methyl3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate

Potassium carbonate (519 mg, 3.76 mmol) was added to a solution ofmethyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (320 mg, 1.88 mmol;CAS no. 318496-66-1 (synthesised according to the method described in WO2012/009009)) and 1-(4-(chloromethyl)benzyl)pyridin-2(1H)-one (527 mg,2.26 mmol) in DMF (5 mL) and heated at 60° C. overnight. The reactionmixture was diluted with EtOAc (50 mL) and washed with brine (2×100 mL),dried over magnesium sulfate, filtered and reduced in vacuo. The crudeproduct was purified by flash chromatography (40 g column, 0-100% EtOAcin isohexanes) to afford two regioisomers. The second isomer off thecolumn was collected to afford methyl3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate(378 mg, 1.01 mmol, 53.7% yield) as a colourless gum.

[MH]⁺=368.2

D.3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylicacid

To methyl3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate(3.77 g, 10.26 mmol) in THF (5 mL) and MeOH (5 mL) was added 2M NaOHsolution (15.39 ml, 30.8 mmol) and stirred at rt overnight. 1M HCl (50mL) was added and extracted with EtOAc (50 mL). The organic layer waswashed with brine (50 mL), dried over magnesium sulfate, filtered andreduced in vacuo to give3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylicacid (1.22 g, 3.45 mmol, 33.6% yield) as a white powder.

[MH]⁺=354.2

G. [4-(4-Methyl-pyrazol-1-ylmethyl)-phenyl]-methanol

4-(Chloromethyl)benzylalcohol (5.47 g, 34.9 mmol) was dissolved inacetone (50 mL). 4-Methylpyrazole (2.86 g, 34.9 mmol) and potassiumcarbonate (5.07 g, 36.7 mmol) were added and the reaction mixture wasstirred at rt for 18 hrs and at 60° C. for 30 hrs after which time thesolvent was removed in vacuo and the residue taken up in EtOAc (100 mL).This solution was washed with water (30 mL), brine (30 mL), dried(MgSO₄) and evaporated in vacuo. The residue was purified by flashchromatography (silica), eluent gradient of 10 to 80% EtOAc iniso-Hexane, fractions combined and evaporated in vacuo to give a whitesolid identified as [4-(4-methyl-pyrazol-1-ylmethyl)-phenyl]-methanol(3.94 g, 18.90 mmol, 54% yield).

[MH]⁺=203

H. 1-(4-Chloromethyl-benzyl)-4-methyl-1H-pyrazole

[4-(4-Methyl-pyrazol-1-ylmethyl)-phenyl]-methanol (2.03 g, 10.04 mmol)and triethylamine (1.13 g, 11.54 mmol) was dissolved in DCM (40 mL). Tothis solution was added methanesulphonyl chloride (1.26 g, 11.04 mmol)dropwise. The reaction mixture was stirred at rt for 18 hrs and dilutedwith CHCl₃ (250 mL). The mixture was washed with saturated NH₄Cl (30mL), water (30 mL), brine (30 mL), dried (Na₂SO₄) and evaporated invacuo. The residue was purified by flash chromatography (silica), eluentgradient of 0 to 60% EtOAc in iso-Hexane, fractions combined andevaporated in vacuo to give a white solid identified as1-(4-chloromethyl-benzyl)-4-methyl-1H-pyrazole (1.49 g, 6.62 mmol, 60%yield).

[MH]⁺=221, 223

M.3-Amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylicacid ethyl ester

1-(4-Bromomethyl-benzyl)-1H-pyridin-2-one (850 mg, 3.06 mmol) wasdissolved in DMF (10 mL). 5-Amino-1H-pyrazole-4-carboxylic acid ethylester (522 mg, 3.36 mmol) and cesium carbonate (1.99 g, 6.11 mmol) wereadded and the reaction mixture was stirred at 50° C. for 18 hrs afterwhich time the reaction mixture was diluted with EtOAc (100 mL). Thissolution was washed with water (30 mL), brine (30 mL), dried (Na₂SO₄)and evaporated in vacuo. The residue was purified by flashchromatography (silica), eluent gradient from 30% Pet Ether/70% EtOAc to100% EtOAc, to afford two regioisomers. The second isomer off the columnwas collected to afford3-amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylicacid ethyl ester (480 mg, 1.36 mmol, 45% yield) as a white solid.

[MH]⁺=353.1

N.3-Amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylicacid

3-Amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylicacid ethyl ester (480 mg, 1.36 mmol) was dissolved in THF (50 mL) andwater (5 mL). Lithium hydroxide (16 3 mg, 6.81 mmol) was added. Thereaction mixture was stirred at 50° C. for 18 hrs after which time thevolatiles were removed in vacuo and the aqueous residue washed withCHCl₃ (150 mL). The aqueous layer was acidified with 1M HCl to pH7 andextracted with CHCl₃ (3×50 mL). The combined extracts were washed withwater (30 mL), brine (30 mL), dried (Na₂SO₄) and evaporated in vacuo togive a white solid identified as3-amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylicacid (370 mg, 1.14 mmol, 84% yield).

[MH]⁺=325.2

P. (2-Fluoro-3-methoxy-benzyl)-carbamic acid tert-butyl ester

2-Fluoro-3-methoxybenzonitrile (500 mg, 3.31 mmol) was dissolved inmethanol (40 mL). This solution was cooled to 0° C. Nickel (II) chloridehexahydrate (79 mg, 0.33 mmol) and di-tertbutyl dicarbonate (1.44 g,6.62 mmol) were added followed by sodium borohydride (876 mg, 23.16mmol) portionwise. The reaction mixture was stirred, allowed to warm tort and stirred for 3 days. The MeOH was removed in vacuo. The residuewas dissolved in CHCl₃ (150 mL), washed with sat NaHCO₃ (aq) (50 mL),water (50 mL), brine (50 mL), dried (Na₂SO₄) and evaporated in vacuo.The residue was purified by chromatography (silica), eluent 20%EtOAc/80% Pet. Ether, to give a white solid identified as(2-fluoro-3-methoxy-benzyl)-carbamic acid tert-butyl ester (540 mg, 0.2mmol, 64% yield).

[MH]⁺=255.8

Q. 2-Fluoro-3-methoxy-benzylamine hydrochloride

(2-Fluoro-3-methoxy-benzyl)-carbamic acid tert-butyl ester (600 mg, 2.35mmol) was dissolved in 4M HCl in dioxan (40 mL). After 2 hrs at rt thesolvent was removed in vacuo to give a pale yellow solid identified as2-fluoro-3-methoxy-benzylamine hydrochloride (414 mg, 2.17 mmol, 92%yield).

[MH]⁺=155.9

T. 1-tert-Butyl 4-ethyl 3-aminopyrazole-1,4-dicarboxylate

To 5-amino-1H-pyrazole-4-carboxylic acid ethyl ester (250 mg, 1.61 mmol)in DCM (10 mL) was added di-tert-butyl dicarbonate (352 mg, 1.61 mmol)and diisopropylethylamine (702 μL, 521 mg, 4.03 mmol) and the reactionstirred at rt overnight. Reaction mixture was diluted with DCM, wateradded, separated, washed with brine, dried (MgSO₄), filtered andconcentrated in vacuo. Flash chromatography afforded 1-tert-butyl4-ethyl 3-aminopyrazole-1,4-dicarboxylate as a white solid (122 mg, 30%yield).

[MH]⁺=256.2

U. Ethyl 3-acetamido-1H-pyrazole-4-carboxylate

A mixture of 1-tert-butyl 4-ethyl 3-aminopyrazole-1,4-dicarboxylate andacetyl chloride was stirred at 0° C. then heated at reflux for 2 hrs.The excess acetyl chloride was removed in vacuo. Water was added and theresulting mixture stirred for 18 hrs at rt. The precipitate wascollected by vacuum filtration and dried to afford ethyl3-acetamido-1H-pyrazole-4-carboxylate as a white solid (46 mg). Theaqueous filtrate was extracted with DCM (4×15 mL) and the combinedorganic layers were dried (MgSO₄), filtered and concentrated in vacuo toafford a further crop of ethyl 3-acetamido-1H-pyrazole-4-carboxylate (48mg) (overall yield 94 mg, 99%).

[MH]⁺=197.8

V. 5-Dimethylamino-1H-pyrazole-4-carboxylic acid ester

5-Amino-1H-pyrazole-4-carboxylic acid ester (1.0 g, 6.45 mmol) wasdissolved in methanol (200 mL) and the solution purged with nitrogen.Formaldehyde (37% by weight, 4.5 mL, 21.18 mmol) was added followed by10% Pd/C (1.0 g). The reaction mixture was shaked on a Parr hydrogenatorat 10 psi for 18 hrs. The reaction mixture was filtered through celiteto remove the catalyst and the residue washed with methanol (200 mL) andwater (20 mL). The combined filtrates were evaporated in vacuo. Thecrude residue was triturated with methanol/diethyl ether and thefiltrate concentrated to afford a colourless oil identified as the titlecompound (1.1 g, 6.00 mmol, 93% yield).

[MH]⁺=183.7

REFERENCE EXAMPLES

Reference examples A to G correspond to examples 1, 2, 3, 41, 77, 83 and126 of our co-pending application PCT/GB2015/053615 (WO2016/083820).

Reference example H corresponds to example 88 of our co-pendingapplication PCT/GB2015/053615 (WO2016/083820).

Reference examples I and J are analogues of examples 7 and 27 ofWO2103/111108.

Reference example K is an analogue of example 79 of the presentapplication.

Reference Example A

N-(3,5-Dimethoxybenzyl)-3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide

To a mixture of3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylicacid (80 mg, 0.226 mmol), (3,5-dimethoxyphenyl)methanamine (45.4 mg,0.272 mmol) and HATU (95 mg, 0.249 mmol) in anhydrous DCM (1.5 mL) andanhydrous DMF (0.3 mL) was added N,N-diisopropylethylamine (99 μl, 0.566mmol) and the mixture allowed to stir at rt overnight. The reaction wasconcentrated in vacuo and the residue purified by flash chromatographyloading in DCM, eluting with a gradient of 1 to 10% MeOH (containing0.3% NH₃)/DCM to afford a gum. This was dissolved in acetonitrile (0.5mL) and water (3 mL) added, forming a precipitate. This was sonicated,then filtered and dried under vacuum to affordN-(3,5-dimethoxybenzyl)-3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide(76 mg, 0.150 mmol, 66.1% yield) as a sticky pale yellow solid.

NMR (d6-DMSO) δ: 3.20 (3H, s), 3.71 (6H, s), 4.32 (2H, d, J=5.8 Hz),4.53 (2H, s), 5.07 (2H, s), 5.28 (2H, s), 6.22 (1H, td, J=6.7, 1.4 Hz),6.37 (1H, t, J=2.3 Hz), 6.40 (1H, dd, J=9.2, 1.4 Hz), 6.44 (2H, d, J=2.3Hz), 7.20-7.29 (4H, m), 7.41 (1H, ddd, J=9.1, 6.6, 2.1 Hz), 7.76 (1H,dd, J=6.8, 2.1 Hz), 8.24 (1H, s), 8.32 (1H, t, J=5.9 Hz).

[MH]⁺=503.3

Reference Example B3-Amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylicacid 2-fluoro-3-methoxy-benzylamide

3-Amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylicacid (75 mg, 0.23 mmol) was dissolved in DCM (20 mL) and DMF (1 ml).This solution was cooled to 0° C. 2-Fluoro-3-methoxy-benzylaminehydrochloride (53 mg, 0.28 mmol) was added followed by HOBt (34 mg, 0.25mmol) and triethylamine (70 mg, 0.69 mmol). Water soluble carbodiimide(53 mg, 0.28 mmol) was then added. The reaction mixture was stirred,allowed to warm to rt and stirred for 3 days. The mixture was dilutedwith chloroform (200 mL) and washed with NaHCO₃ (aq) (50 mL), water (50mL) and brine (50 mL), dried (Na₂SO₄) and evaporated in vacuo. Theresidue was purified by flash chromatography (silica), eluent 4%MeOH/96% CHCl₃, to give a white solid identified as3-amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylicacid 2-fluoro-3-methoxy-benzylamide (92 mg, 0.20 mmol, 86% yield).

[MH]⁺=462.2

¹H NMR: (d6-DMSO) δ: 3.82 (3H, s), 4.36 (2H, d, J=5.7 Hz), 5.04 (2H, s),5.07 (2H, s), 5.38 (2H, s), 6.21-6.24 (1H, m), 6.39 (1H, t, J=0.7 Hz),6.86-6.87 (1H, m), 7.04-7.07 (2H, m), 7.20 (2H, d, J=8.1 Hz), 7.26 (2H,d, J=8.1 Hz), 7.39-7.43 (1H, m), 7.76 (1H, dd, J=6.6, 1.6 Hz), 8.00 (1H,s), 8.27 (1H, t, J=5.9 Hz).

Reference Example C1-(7-Chloro-quinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylicacid 2-fluoro-3-methoxy-benzylamide

(7-Chloro-quinolin-3-yl)-methanol

7-Chloroquinoline-3-carboxylic acid (500 mg, 2.4 mmol) was dissolved inanhydrous THF (20 mL) and cooled to −20° C. To this solution was addedtriethylamine (1.0 mL, 7.23 mmol) and isobutyl chloroformate (0.38 mL,2.9 mmol). The reaction mixture was stirred at −20° C. for 20 min andthen poured into a solution of sodium borohydride (731 mg, 19 mmol) inwater (2 mL) at 0° C. The reaction mixture was allowed to warm to rt andstirred for 18 hours. The mixture was diluted with EtOAc (50 mL) and thelayers separated. The organic layer was washed with water (20 mL), brine(20 mL), dried (Na₂SO₄), filtered and evaporated in vacuo to give ayellow solid. The solid was purified by chromatography on silica,eluting with EtOAc/Pet Ether to afford (7-chloro-quinolin-3-yl)-methanolas an off white solid, 134 mg, 29% yield.

[MH]⁺=194.1

3-Bromomethyl-7-chloro-quinoline

(7-Chloro-quinolin-3-yl)-methanol (134 mg, 0.692 mmol) was dissolved inDCM (5 mL). PBr₃ (65 μL, 0.692 mmol) was added and the reaction stirredfor 3 hrs at rt. Upon completion, the reaction mixture was quenched withdilute NaHCO₃ (aq) (10 mL). The layers were separated and the organicwashed with water (10 mL) and brine (10 mL). The organic layer was dried(MgSO₄), filtered and concentrated in vacuo to afford a yellow solididentified as 3-bromomethyl-7-chloro-quinoline (78 mg, 44% yield).

[MH]⁺=257.6

1-(7-Chloro-quinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylicacid methyl ester

Methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (51 mg, 0.304 mmol;CAS no. 318496-66-1 (synthesised according to the method described in WO2012/009009)) was taken up in DMF (2 mL) and treated with potassiumcarbonate (84 mg, 0.608 mmol) and 3-bromomethyl-7-chloro-quinoline (78mg, 0.304 mmol). The reaction was stirred overnight at rt. EtOAc (60 mL)and water (20 mL) were added and the layers separated. The organic layerwas washed with water (3×10 mL), brine (10 mL), dried (MgSO₄), filteredand evaporated in vacuo. The residue was purified by chromatography,eluting with EtOAc/Pet.Ether to afford two isomeric products. The fasterrunning product was identified as the undesired regioisomer. The slowerrunning product afforded a yellow oil and was identified as1-(7-chloro-quinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylicacid methyl ester (53 mg, 50% yield).

[MH]⁺=345.8

1-(7-Chloro-quinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylicacid

To1-(7-chloro-quinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylicacid methyl ester (53 mg, 0.153 mmol) in ethanol (10 mL) was addedsodium hydroxide (61 mg, 1.53 mmol) and the reaction was heated atvigorous reflux for 4.5 hrs. The mixture was cooled and concentrated invacuo. The residue was diluted with water (5 mL), adjusted to pH 3.6with 2M HCl and extracted with 90% chlorofrom/10% iso-propyl alcohol(6×15 mL). The combined organic layers were dried (Na₂SO₄), filtered andconcentrated in vacuo to give1-(7-chloro-quinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylicacid as a pale yellow solid (50 mg, 98% yield).

[MH]⁺=332

1-(7-Chloro-quinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylicacid 2-fluoro-3-methoxy-benzylamide

1-(7-Chloro-quinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylicacid (25 mg, 0.075 mmol) was taken up in DCM (5 mL) at 0° C. To thesolution was added triethylamine (52 μL, 0.377 mmol), HOBt (12 mg, 0.09mmol) and water soluble carbodiimide (20 mg, 0.106 mmol). After 15 min,2-fluoro-3-methoxy-benzylamine hydrochloride (14 mg, 0.075 mmol) wasadded and the reaction allowed to warm to rt and stirred for over theweekend. The reaction was diluted with CHCl₃ (50 ml) and washed withsat. aq. NaHCO₃ (20 ml) followed by water (20 mL) and brine (20 mL). Theorganic layer was dried (MgSO₄), filtered and concentrated in vacuo. Thecrude product was purified by chromatography eluting with 6%Methanol/94% DCM to give a white solid (16 mg, 45% yield) identified as1-(7-chloro-quinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylicacid 2-fluoro-3-methoxy-benzylamide.

[MH]⁺=469

¹H NMR (DMSO): 3.20 (3H, s), 3.82 (3H, s), 4.41 (2H, d, J=5.8 Hz), 4.54(2H, s), 5.57 (2H, s), 6.87-6.91 (1H, m), 7.03-7.09 (2H, m), 7.67 (1H,dd, J=8.8, 2.1 Hz), 8.07 (1H, d, J=8.8 Hz), 8.10 (1H, d, J=1.9 Hz), 8.30(1H, d, J=1.7 Hz), 8.37 (1H, s), 8.39 (1H, t, J=5.8 Hz), 8.92 (1H, d,J=2.2 Hz)

Reference Example D 3-Fluoro-4-methoxy-pyridine-2-carbonitrile

To a large microwave vial, cyanocopper (1.304 g, 14.56 mmol) was addedto a solution of 2-bromo-3-fluoro-4-methoxypyridine (1 g, 4.85 mmol) inDMF (5 mL). The reaction vial was sealed and heated to 100° C. for 16hrs. The reaction mixture was diluted with water (20 mL) and EtOAc (20mL). The thick suspension was sonicated and required additional water(40 mL) and EtOAc (2×50 mL) with sonication to break-up the solidprecipitated. The combined layers were filtered through a plug of celiteand the organic layer isolated, washed with brine (50 mL), dried overmagnesium sulfate, filtered and the solvent removed under reducedpressure to give a pale green solid identified as the desired compound3-fluoro-4-methoxy-pyridine-2-carbonitrile (100 mg, 0.578 mmol, 12%yield)

(3-Fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester

3-Fluoro-4-methoxy-pyridine-2-carbonitrile (100 mg, 0.578 mmol) wasdissolved in anhydrous methanol (10 mL, 247 mmol) and nickel chloridehexahydrate (14 mg, 0.058 mmol) was added followed by di-tert-butyldicarbonate (255 mg, 1.157 mmol). The resulting pale green solution wascooled in an ice-salt bath to −5° C. and then sodium borohydride (153mg, 4.05 mmol) was added portionwise maintaining the reactiontemperature 0° C. The deep brown solution was left to stir at 0° C. andslowly allowed to warm to rt and then left to stir at rt for 3 hrs. Thereaction mixture was evaporated to dryness at 40° C. to afford a blackresidue which was diluted with DCM (10 mL) and washed with sodiumhydrogen carbonate (10 mL). An emulsion formed so the organics wereseparated via a phase separating cartridge and concentrated. The crudeliquid was purified by chromatography eluting with EtOAc/iso-Hexane toafford the title compound,(3-fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl esteras a clear yellow oil (108 mg, 62% yield)

[MH]⁺=257

C-(3-Fluoro-4-methoxy-pyridin-2-yl)-methylamine hydrochloride salt

(3-Fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester(108 mg, 0.358 mmol) was taken up in iso-propyl alcohol (1 mL) and thenHCl (6N in iso-propyl alcohol) (1 mL, 0.578 mmol) was added at rt andleft to stir at 40° C. for 2 hours. The reaction mixture wasconcentrated under reduced pressure and then triturated with ether,sonicated and then decanted to give a cream coloured solid (75 mg, 55%yield) identified as C-(3-fluoro-4-methoxy-pyridin-2-yl)-methylaminehydrochloride salt.

[MH]⁺=157

3-Methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylicacid (3-fluoro-4-methoxy-pyridin-2-ylmethyl)-amide

3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylicacid (75 mg, 0.212 mmol),C-(3-Fluoro-4-methoxy-pyridin-2-yl)-methylamine hydrochloride salt (49mg, 0.212 mmol) and HATU (89 mg, 0.233 mmol) were suspended in anhydrousDCM (3 mL) to which triethylamine (177 μL, 1.270 mmol) was added,sonicated and then left to stir at rt for 4 hours. The solvent wasremoved under reduced pressure and the resulting residue was quenchedwith ammonium chloride solution (5 mL).

An off white solid resulted which was sonicated, filtered under reducedpressure washed with water and then placed in the vac oven at 40° C.overnight. The crude material was purified by chromatography elutingwith (1% ammonia-methanol)/DCM to afford the3-methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylicacid (3-fluoro-4-methoxy-pyridin-2-ylmethyl)-amide as a white solid (67mg, 64% yield)

[MH]⁺=492

NMR (d⁶-DMSO) δ: 3.25 (3H, s), 3.92 (3H, s), 4.46-4.57 (4H, m), 5.07(2H, s), 5.28 (2H, s), 6.22 (1H, td, J=1.4, 6.7 Hz), 6.39 (1H, ddd,J=0.7, 1.4, 9.2 Hz), 7.17-7.28 (5H, m), 7.41 (1H, ddd, J=2.1, 6.6, 8.9Hz), 7.75 (1H, ddd, J=0.7, 2.1, 6.8 Hz), 8.21-8.29 (2H, m), 8.42 (1H, t,J=5.4 Hz)

Reference Example E 6-Bromo-2-fluoro-3-methoxy-benzoic acid

To a suspension of 2-fluoro-3-methoxybenzoic acid (10 g, 58.8 mmol) inacetic acid (50 mL) and water (50 mL) at rt was added bromine (6.06 mL,118 mmol) dropwise. The reaction was then heated to 60° C. for 1 hr. Thereaction was cooled to room temperature and the white precipitate wasfiltered. The solid was washed with water (200 mL) and iso-Hexane (50mL) to give 6-bromo-2-fluoro-3-methoxy-benzoic acid as white solid,12.098 g, 82% yield.

[MH]⁺=249/251

(6-Bromo-2-fluoro-3-methoxy-phenyl)-methanol

To a stirred solution of 6-bromo-2-fluoro-3-methoxy-benzoic acid (4.13g, 16.58 mmol) in THF (20 mL) was added 4-methylmorpholine (1.914 mL,17.41 mmol) and then isobutyl chloroformate (2.15 mL, 16.58 mmol). After1 hour the reaction mixture was filtered to remove any salts generated,the solid was washed with additional THF (10 mL). The filtrate andwashings were combined and cooled to 0° C. in an ice bath and then NaBH₄(0.659 g, 17.41 mmol) in cold water (10 mL) was added in one portion(gas evolved), then allowed to warm to room temperature and stirred for2 hours. The reaction mixture was quenched by careful addition of 1M HCl(30 mL) until acidic pH was obtained. The product was extracted intodiethyl ether (150 mL). The organic layer was then washed with 2M NaOH(2×100 mL) to removed starting carboxylic acid, then acidified bywashing with 1M HCl (100 mL), followed by brine (100 mL), dried overmagnesium sulfate, filtered and solvent removed in vacuo. The crudeproduct was purified by chromatography eluting with 0-50%EtOAc/iso-Hexane to afford (6-bromo-2-fluoro-3-methoxy-phenyl)-methanolas a colourless oil, 1.37 g, 50% yield.

[MH]⁺=217/219

1-Bromo-2-chloromethyl-3-fluoro-4-methoxy-benzene

A solution of (6-bromo-2-fluoro-3-methoxy-phenyl)-methanol (500 mg,2.127 mmol) in anhydrous DCM (4 mL) was treated with triethylamine (415μL, 2.98 mmol), followed by methanesulfonyl chloride (214 μL, 2.77mmol). The mixture was allowed to stir at ambient temperature overnight.The reaction mixture was partitioned between DCM (50 mL) and sat. aq.NH₄Cl (40 mL). The organic layer was collected and the aqueous layerextracted with further DCM (40 mL). The combined organics were washedwith water (40 mL), brine (40 mL), dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by chromatography elutingwith a gradient of 0 to 30% EtOAc/iso-Hexane to afford1-bromo-2-chloromethyl-3-fluoro-4-methoxy-benzene (468 mg, 86% yield) asa white solid.

2-(6-Bromo-2-fluoro-3-methoxy-benzyl)-isoindole-1,3-dione

To a solution of 1-bromo-2-chloromethyl-3-fluoro-4-methoxy-benzene (460mg, 1.815 mmol) in anhydrous DMF (5 mL) was added potassium phthalimide(403 mg, 2.178 mmol) and the mixture heated at 90° C. overnight. Themixture was diluted with EtOAc (75 mL) and washed with water (3×35 mL),brine (35 mL), dried (Na₂SO₄), filtered and concentrated to a yellowsolid. The crude material was purified by flash chromatography, elutingwith a gradient of 0 to 50% EtOAc/iso-Hexane. The desired product2-(6-bromo-2-fluoro-3-methoxy-benzyl)-isoindole-1,3-dione was isolatedas white needles, 372 mg, 56% yield.

[MH]⁺=364.0/366.0

6-Bromo-2-fluoro-3-methoxy-benzylamine

A suspension of2-(6-bromo-2-fluoro-3-methoxy-benzyl)-isoindole-1,3-dione (0.368 g,1.011 mmol) in methanol (7.5 mL) was treated with hydrazine hydrate(0.064 mL, 1.314 mmol) and the reaction mixture heated at reflux for 5hrs. The crude mixture was loaded directly onto an SCX column (8 g),washed with MeOH and eluted with 1% NH₃/MeOH to afford6-bromo-2-fluoro-3-methoxy-benzylamine (204 mg, 85% yield) as a yellowoil

[MH]⁺=233.9/235.9

3-Methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylicacid 6-bromo-2-fluoro-3-methoxy-benzylamide

A 25 mL flask was charged with3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylicacid (130 mg, 0.368 mmol), (6-bromo-2-fluoro-3-methoxy-benzylamine (86mg, 0.368 mmol), HATU (154 mg, 0.405 mmol), anhydrous DCM (3 mL) andanhydrous DMF (0.5 mL). N,N-Disopropylethylamine (160 μL, 0.920 mmol)was added and the mixture allowed to stir at ambient temperatureovernight. The reaction was concentrated under vacuum and redissolved inMeOH (4 mL) then purified by SCX, washing with MeOH, eluting with 1%NH₃/MeOH. The residue was further purified chromatography eluting with agradient of 0 to 10% MeOH (containing 0.3% NH₃)/DCM to afford3-methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylicacid 6-bromo-2-fluoro-3-methoxy-benzylamide (191 mg, 89% yield) as awhite foam.

[MH]⁺=569.2/571.2

3-Methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylicacid 6-cyano-2-fluoro-3-methoxy-benzylamide

To a degassed solution of dicyanozinc (24.13 mg, 0.205 mmol) and3-methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylicacid 6-bromo-2-fluoro-3-methoxy-benzylamide (90 mg, 0.158 mmol) indimethylacetamide (1.2 mL) was addedtetrakis(triphenylphosphine)palladium(0) (18.26 mg, 0.016 mmol) and themixture heated to 110° C. overnight. The mixture was purified bychromatography eluting with a gradient of 0 to 10% (0.3% NH₃/MeOH)/DCMto give3-methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylicacid 6-cyano-2-fluoro-3-methoxy-benzylamide as a pale yellow foam, 21mg, 25% yield.

[MH]⁺=516.3

¹H NMR (d⁶-DMSO) δ: 3.21 (3H, s), 3.92 (3H, s), 4.47-4.55 (4H, m), 5.06(2H, s), 5.27 (2H, s), 6.21 (1H, td, J=6.7, 1.4 Hz), 6.39 (1H, d, J=9.1Hz), 7.17-7.31 (5H, m), 7.40 (1H, ddd, J=8.9, 6.6, 2.1 Hz), 7.67 (1H,dd, J=8.6, 1.5 Hz), 7.75 (1H, dd, J=6.8, 2.1 Hz), 8.20 (1H, s), 8.40(1H, t, J=5.2 Hz)

Reference Example F 2-Chloro-3-fluoro-6-methoxy-benzaldehyde

To an ice-salt cooled flask containing methanol (8 mL, 198 mmol) wasslowly added sodium hydride (1.318 g, 33.0 mmol). Once the addition wascomplete the cooling bath was removed and then allowed to warm to rt. Ina second vessel (250 mL flask), 2-chloro-3,6-difluorobenzaldehyde (5 g,27.5 mmol) was dissolved in a mixture of anhydrous methanol (60 mL, 1483mmol) and THF (25 mL, 305 mmol) and warmed to 60° C. Whilst at 60° C.the sodium methoxide solution was slowly added to the reaction mixture.Once the addition was complete the reaction mixture was left to heat at60° C. overnight. The solvent was removed under reduced pressure to givea bright yellow solid which was quenched with water (100 mL), sonicatedand then left to stir for 30 min. The resulting yellow solid wasfiltered, washed with water and then left to dry under reduced pressurebefore transferring to a vacuum oven at 40° C. overnight. The crude waspurified by chromatography eluting with EtOAc/iso-Hexane to afford thedesired compound 2-chloro-3-fluoro-6-methoxy-benzaldehyde as an offwhite solid, 3.19 g, 61% yield.

[MH]⁺=189/191

2-Chloro-3-difluoromethyl-1-fluoro-4-methoxy-benzene

2-Chloro-3-fluoro-6-methoxy-benzaldehyde (2 g, 10.61 mmol) was dissolvedin anhydrous DCM (30 mL, 466 mmol) under a nitrogen filled balloon andcooled in a salt-ice bath. To the solution diethylaminosulfurtrifluoride (4.20 mL, 31.8 mmol) was added dropwise to form a yellowsolution. The reaction was stirred at 0° C. for 5 min and then thecooling bath was removed and the reaction allowed to warm to rtovernight. The reaction mixture was slowly quenched into saturatedsodium hydrogen carbonate (100 mL), the organic layer was separated,washed with brine (100 mL) and dried using a phase separating cartridge.The solvent was removed under reduced pressure to give an orange oil,which was purified by chromatography eluting with EtOAc/iso-Hexane.2-Chloro-3-difluoromethyl-1-fluoro-4-methoxy-benzene (1.0 g, 43% yield)was isolated as a pale yellow oil which solidified on standing.

2-Difluoromethyl-6-fluoro-3-methoxy-benzonitrile

2-Chloro-3-difluoromethyl-1-fluoro-4-methoxy-benzene (1 g, 4.75 mmol)was dissolved in anhydrous dimethylacetamide (7 mL, 74.7 mmol) to whichdicyanozinc (0.558 g, 4.75 mmol) was added. Nitrogen was bubbled intothe reaction mixture for 20 min then,tris(dibenzylideneacetone)dipalladium(0) (0.087 g, 0.095 mmol) and[1,1′bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (0.139 g, 0.190 mmol) were added. The reaction mixturewas heated at 150° C. overnight under an atmosphere of nitrogen. Thereaction mixture was quenched into water (100 mL) and then extractedwith EtOAc (3×200 mL). The combined organics were washed with brine(3×200 mL), dried over magnesium sulphate, filtered and evaporated underreduced pressure to give a dark brown oil. The crude product waspurified by chromatography eluting with EtOAc/iso-Hexane to afford2-difluoromethyl-6-fluoro-3-methoxy-benzonitrile (182 mg, 17% yield) asa brown solid.

[MH]⁺=202.1

(2-Difluoromethyl-6-fluoro-3-methoxy-benzyl)-carbamic acid tert-butylester

2-(Difluoromethyl)-6-fluoro-3-methoxy-benzonitrile (182 mg, 0.778 mmol)was dissolved in anhydrous methanol (5 mL, 124 mmol) to which NickelChloride hexahydrate (19 mg, 0.078 mmol) was added followed bydi-tert-butyl dicarbonate (343 mg, 1.556 mmol). The resulting pale greensolution was cooled in an ice-salt bath to −5° C. and then sodiumborohydride (206 mg, 5.45 mmol) was added portionwise, maintaining thereaction temperature ˜0° C. The deep brown solution was left to stir at0° C. and slowly allowed to warm to rt overnight. The solvent wasremoved under reduced pressure and then partitioned between DCM (10 mL)and water (10 mL). The aqueous was re-extracted with DCM (2×10 mL). Thecombined organics were washed brine (10 mL), dried using a phaseseparating cartridge and concentrated in vacuo. The crude product waspurified by chromatography eluting with EtOAc/iso-Hexane to give(2-difluoromethyl-6-fluoro-3-methoxy-benzyl)-carbamic acid tert-butylester as a white waxy solid (158 mg, 63% yield).

[MNa]⁺=328

2-Difluoromethyl-6-fluoro-3-methoxy-benzylamine hydrochloride

(2-Difluoromethyl-6-fluoro-3-methoxy-benzyl)-carbamic acid tert-butylester (158 mg, 0.492 mmol) was taken up in iso-propyl alcohol (1 mL) andthen HCl (6N in iso-propyl alcohol) (1 mL, 0.778 mmol) was added andstirred at 40° C. for 1 hour. An off white precipitate formed and wascollected via vacuum filtration and washed with iso-propyl alcohol (1mL) to give the desired product2-difluoromethyl-6-fluoro-3-methoxy-benzylamine hydrochloride as an offwhite solid (43 mg, 22% yield).

[MH]⁺=206

3-Methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylicacid 2-difluoromethyl-6-fluoro-3-methoxy-benzylamide

3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylicacid (58 mg, 0.162 mmol),2-difluoromethyl-6-fluoro-3-methoxy-benzylamine hydrochloride salt (40.2mg, 0.163 mmol) and HATU (68.3 mg, 0.180 mmol) were suspended inanhydrous DCM (3 mL) to which triethylamine (91 μL, 0.653 mmol) wasadded, sonicated and then left to stir at rt for 3 hrs. The solvent wasremoved under reduced pressure and the residue quenched with ammoniumchloride solution (5 mL), resulting in a pale brown solid which was leftto stir rt over the weekend. The solid was filtered under reducedpressure washed with water, dried under reduced pressure and then placedin the desiccator at 50° C. for 3 hours. The desired product,3-ethoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylicacid 2-difluoromethyl-6-fluoro-3-methoxy-benzylamide (74 mg, 83% yield)was isolated as a free flowing cream solid.

[MH]⁺=541.2

NMR (d⁶-DMSO) δ 3.12 (3H, s), 3.83 (3H, s), 4.43 (2H, s), 4.52-4.59 (2H,m), 5.05 (2H, s), 5.25 (2H, s), 6.21 (1H, td, J=1.4, 6.7 Hz), 6.39 (1H,dt, J=1.0, 9.2 Hz), 7.15-7.44 (8H, m), 7.75 (1H, ddd, J=0.7, 2.1, 6.8Hz), 8.08 (1H, t, J=4.9 Hz), 8.22 (1H, s)

Reference Example G 5-Bromomethyl-2-fluoro-pyridine

2-Fluoro-5-methylpyridine (5.0 g, 45 mmol) was dissolved in1,2-dichloroethane (120 mL). To this solution was addedN-bromosuccinimide (9.61 g, 54 mmol) and azobisisobutyronitrile (739 mg,4.5 mmol). The reaction was stirred at reflux (95° C.) for 5 hours thenthe reaction was cooled to rt. The reaction mixture was diluted withCHCl₃ (50 mL) and was washed with sat. NaHCO₃ (1×20 mL), water (1×20mL), followed by brine (1×20 mL), dried (Na₂SO₄) and filtered through PSpaper and evaporated in vacuo. The residue was purified bychromatography (silica), eluting with 10% EtOAc, 90% Pet. Ether, to givea colourless oil identified as 5-bromomethyl-2-fluoro-pyridine, 5.9 g,69% yield.

[MH]⁺=191.876

NMR (CDCl3): 4.46 (2H, s), 6.93 (1H, dd, J=8.4, 3.0 Hz), 7.84 (1H, td,J=7.8, 2.6 Hz), 8.23 (1H, d, J=2.2 Hz)

1-(6-Fluoro-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylicacid ethyl ester

Ethyl 3-trifluoromethyl-1H-pyrazole-4-carboxylate (1.57 g, 7.53 mmol)was dissolved in DMF (20 mL), 5-Bromomethyl-2-fluoro-pyridine (1.3 g,6.84 mmol) and cesium carbonate (6.69 g, 20.53 mmol) were added. Thereaction mixture was stirred at 50° C. for 18 hours after which time thereaction mixture was diluted with EtOAc (100 mL), this solution waswashed with water (1×30 mL), brine (1×30 mL), dried (Na₂SO₄) andfiltered through PS paper and evaporated in vacuo. The residue waspurified by chromatography (silica), eluting with 85% Pet. Ether, 15%EtOAc to give a white foamy solid (1.26 g, 58% yield) identified as1-(6-fluoro-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylicacid ethyl ester.

[MMeCN]⁺=358.75

1-(6-Fluoro-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylicacid

1-(6-Fluoro-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylicacid ethyl ester (1.26 g, 3.97 mmol) was dissolved in THF (50 mL) andwater (5 mL) then lithium hydroxide (476 mg, 19.86 mmol) were added. Thereaction mixture was stirred at 50° C. for 18 hrs after which time thesolvent was concentrated in vacuo and the residue taken up in EtOAc (50mL). The aqueous layer was extracted and acidified with 1M HCl to pH2and extracted with CHCl₃ (3×50 mL). The combined extracts were washedwith water (1×30 mL) followed by brine (1×30 mL), dried (Na₂SO₄) andfiltered through PS paper and evaporated in vacuo. The residue waspurified by chromatography (silica), eluting with 3% MeOH, 97% CHCl₃, togive a colourless oil identified as1-(6-fluoro-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylicacid, 946 mg, 82% yield.

[MH]⁺=289.82

1-(6-Pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylicacid

1-(6-Fluoro-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylicacid (300 mg, 1.04 mmol) was dissolved in dioxane (25 mL) andpyrrolidine (2 mL) and the reaction mixture was stirred at 80° C. for 18hrs. Upon completion the reaction mixture was diluted with EtOAc (100mL), this solution was washed with water (1×30 mL), brine (1×30 mL),dried (Na₂SO₄) and filtered through PS paper and evaporated in vacuo.The residue was purified by chromatography eluting with 1% AcOH, 9%MeOH, 90% CHCl₃ to give a white foamy solid (267 mg, 76% yield)identified as1-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylicacid.

[MH]⁺=340.72

1-(6-Pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylicacid 2-fluoro-3-methoxy-benzylamide

2-Fluoro-3-methoxy-benzylamine hydrochloride (56 mg, 0.294 mmol) and1-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylicacid (100 mg, 0.294 mmol) were combined and taken up in DCM (10 mL) at0° C. To the solution was added HOBt (48 mg, 0.353 mmol), triethylamine(205 μL, 1.469 mmol) and water soluble carbodiimide (79 mg, 0.411 mmol).The reaction was allowed to warm to rt and stirred for 3 days. Thereaction was diluted with CHCl₃ (50 mL) and sat. aq. NaHCO₃ (20 mL) wasadded. The organic layer was separated, dried (MgSO₄), filtered andconcentrated. The crude product was purified by chromatography elutingwith MeOH/DCM to afford the desired product1-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylicacid 2-fluoro-3-methoxy-benzylamide as a white solid, 95 mg, 68% yield.

[MH]⁺=478.0

¹H NMR (DMSO) δ: 1.90-1.94 (4H, m), 3.31-3.37 (4H, m), 3.82 (3H, s),4.39 (2H, d, J=5.6 Hz), 5.26 (2H, s), 6.44 (1H, d, J=8.6 Hz), 6.85-6.90(1H, m), 7.03-7.10 (2H, m), 7.50 (1H, dd, J=8.8, 2.4 Hz), 8.14 (1H, d,J=2.3 Hz), 8.36 (1H, d, J=0.6 Hz), 8.74 (1H, t, J=5.8 Hz)

Reference Example HN-{[2-Fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide

[M+H]⁺=529.3

1H NMR: (d6-DMSO) 3.18 (3H, s), 4.26 (2H, d, J=5.0 Hz), 4.42 (2H, s),5.06 (2H, s), 5.24 (2H, s), 6.19-6.23 (1H, m), 6.38 (1H, d, J=9.2 Hz),7.19 (2H, d, J=8.1 Hz), 7.24 (2H, d, J=8.2 Hz), 7.38-7.45 (2H, m),7.56-7.65 (2H, m), 7.74 (1H, dd, J=6.8, 1.8 Hz), 8.11 (1H, s), 8.18 (1H,t, J=5.2 Hz), 9.84 (1H, s)

IC50 (human PKaI)=1.1 nM

IC50 (human KLK1)=>40,000 nM

Reference Example I

An analogue of example 7 from WO 2013/111108

Reference Example J

An analogue of example 27 from WO 2013/111108

Reference Example K

An analogue of example 79 of the present application.

EXAMPLES OF THE PRESENT INVENTION Example 39N-{[2-Fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide

A. 6-tert-Butoxycarbonylamino-2-fluoro-3-methoxy-benzoic acid methylester

Methyl 6-bromo-2-fluoro-3-methoxybenzoate (2.0 g, 7.6 mmol) wasdissolved in dioxan (50 mL). tert-Butyl carbamate (980 mg, 8.4 mmol),4,5-(bis(diphenylphospheno)-9,9-dimethylxanthene (440 mg, 0.76 mmol),palladium (II) acetate (171 mg, 0.76 mmol) and cesium carbonate (4.95 g,15.2 mmol) were added and the reaction mixture was stirred under anatmosphere of nitrogen at 100° C. for 18 hrs after which time thereaction mixture was diluted with EtOAc (100 mL), filtered throughCelite and the residue washed with EtOAc (50 mL). The combined filtrateswere evaporated in vacuo. The residue was purified by flashchromatography (silica), eluent 10% EtOAc, 90% Pet Ether to give ayellow oil which solidified on standing and was identified as6-tert-butoxycarbonylamino-2-fluoro-3-methoxy-benzoic acid methyl ester(2.09 g, 6.97 mmol, 92%).

B. (3-Fluoro-2-hydroxymethyl-4-methoxy-phenyl)-carbamic acid tert-butylester

6-tert-Butoxycarbonylamino-2-fluoro-3-methoxy-benzoic acid methyl ester(480 mg, 1.6 mmol) was dissolved in THF (50 mL) and cooled to 0° C.under nitrogen. A 2M solution of lithium borohydride in THF (1.6 mL,3.21 mmol) was added dropwise. After 18 hrs at rt saturated aqueousammonium chloride was added slowly and the reaction mixture extractedwith EtOAc (3×50 mL). The combined organic extracts were washed withwater (1×30 mL), brine (1×30 mL), dried (Na₂SO₄) and evaporated invacuo. The residue was purified by flash chromatography (silica), eluent60% EtOAc, 40% Pet Ether to give a white solid identified as(3-fluoro-2-hydroxymethyl-4-methoxy-phenyl)-carbamic acid tert-butylester (426 mg, 1.57 mmol, 98%).

[MH]⁺=277.7

C. (6-Amino-2-fluoro-3-methoxy-phenyl)-methanol

(3-Fluoro-2-hydroxymethyl-4-methoxy-phenyl)-carbamic acid tert-butylester (426 mg, 1.57 mmol) was dissolved in 4M HCl in dioxan (50 mL).After one hour at rt the solvent was removed in vacuo to give a whitesolid identified as (6-amino-2-fluoro-3-methoxy-phenyl)-methanol (320mg, 1.54 mol, 98%).

D. (2-Fluoro-3-methoxy-6-tetrazol-1-yl-phenyl)-methanol

(6-Amino-2-fluoro-3-methoxy-phenyl)-methanol (320 mg, 1.54 mmol) wasdissolved in acetic acid (20 mL). Trimethyl orthoformate (491 mg, 4.62mmol) and sodium azide (301 mg, 4.62 mmol) were added. The reactionmixture was stirred at rt for 18 hrs after which time the reactionmixture was poured into water (50 mL) and extracted with EtOAc (2×100mL). This solution was washed with water (1×30 mL), brine (1×30 mL),dried (Na₂SO₄) and evaporated in vacuo. The residue was purified byflash chromatography (silica), eluent 60% EtOAc, 40% Pet Ether to give ayellow oil identified as(2-fluoro-3-methoxy-6-tetrazol-1-yl-phenyl)-methanol (160 mg, 0.71 mmol,46%).

[M+H]⁺=225.2

E. 1-(2-Bromomethyl-3-fluoro-4-methoxy-phenyl)-1H-tetrazole

(2-Fluoro-3-methoxy-6-tetrazol-1-yl-phenyl)-methanol (160 mg, 0.71 mmol)was dissolved in dichloromethane (50 mL). To this solution was addedphosphorous tribromide (386 mg, 1.43 mmol). The reaction mixture wasstirred at rt for 18 hrs and diluted with CHCl₃ (100 mL), washed withsat. NaHCO₃ (1×30 mL), water (1×30 mL), brine (1×30 mL), dried (Na₂SO₄)and evaporated in vacuo to give a white solid identified as1-(2-bromomethyl-3-fluoro-4-methoxy-phenyl)-1H-tetrazole which was usedwithout further purification (204 mg, 71 mmol, 100%).

[M+H+MeCN]⁺=330.1

F. 1-(2-Azidomethyl-3-fluoro-4-methoxy-phenyl)-1H-tetrazole

1-(2-Bromomethyl-3-fluoro-4-methoxy-phenyl)-1H-tetrazole (205 mg, 0.71mmol) was dissolved in DMF (20 mL). Sodium azide (93 mg, 1.43 mmol) wasadded. The reaction mixture was stirred at rt for 18 hrs after whichtime the reaction mixture was diluted with EtOAc (100 mL). This solutionwas washed with water (1×30 mL), brine (1×30 mL), dried (Na₂SO₄) andevaporated in vacuo. The residue was purified by flash chromatography(silica), eluent 60% Pet Ether, 40% EtOAc to give a white solididentified as 1-(2-azidomethyl-3-fluoro-4-methoxy-phenyl)-1H-tetrazole(128 mg, 0.51 mmol, 72%).

[M+H+MeCN]⁺=291.2

G. 2-Fluoro-3-methoxy-6-tetrazol-1-yl-benzylamine

1-(2-Azidomethyl-3-fluoro-4-methoxy-phenyl)-1H-tetrazole (128 mg, 0.51mmol) was dissolved in MeOH (40 mL) This solution was hydrogenated over10% Pd/C (50 mg) at atmospheric pressure for 2 hrs after which time thecatalyst was filtered off through Celite and the residue washed withMeOH (100 mL). The combined filtrates were evaporated in vacuo to give ayellow oil identified as 2-fluoro-3-methoxy-6-tetrazol-1-yl-benzylamine(100 mg, 0.45 mmol, 87%).

H.N-{[2-Fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide

3-Methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylicacid (65 mg, 0.18 mmol) was dissolved in DCM (30 mL).(2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (84 mg, 0.22 mmol) and N,N-diisopropylethyamine (48mg, 0.37 mmol) were added at rt. After 20 min2-fluoro-3-methoxy-6-tetrazol-1-yl-benzylamine (43 mg, 0.19 mmol) wasadded and the reaction mixture stirred at rt for 18 hrs. The reactionmixture was diluted with CHCl₃ (50 mL) and washed with sat NaHCO₃ (aq)(1×30 mL), water (1×30 mL), brine (1×30 mL), dried (Na₂SO₄) andevaporated in vacuo to give a yellow oil. The residue was purified byflash chromatography (silica), eluent 5% MeOH, 95% CHCl₃ to give a whitesolid identified as the title compound (111 mg, 0.2 mmol, 47%).

[MH]⁺=559.4

¹H NMR: (d6-DMSO) δ: 3.18 (3H, s), 3.94 (3H, s), 4.22 (2H, d, J=4.8 Hz),4.41 (2H, s), 5.06 (2H, s), 5.24 (2H, s), 6.20-6.23 (1H, m), 6.39 (1H,d, J=9.0 Hz), 7.19 (2H, d, J=8.2 Hz), 7.24 (2H, d, J=8.2 Hz), 7.33-7.43(3H, m), 7.75 (1H, dd, J=6.8, 1.9 Hz), 8.11 (1H, s), 8.15 (1H, t, J=5.2Hz), 9.73 (1H, s)

Example 861-{[2-(3,3-Difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide

A. 2-(3,3-Difluoro-pyrrolidin-1-yl)-pyrimidine-5-carboxylic acid ethylester

Ethyl-2-chloropyrimidine-5-carboxylate (1.5 g, 8.04 mmol) was dissolvedin dioxan (50 mL). 3,3-Difluoropyrrolidine hydrochloride (1.73 g, 12.06mmol) and triethylamine (2.44 g, 24.1 mmol) were added and the reactionmixture was stirred at 80° C. for 18 hrs after which time the reactionmixture was diluted with EtOAc (100 mL). This solution was washed withwater (1×30 mL), brine (1×30 mL), dried (Na₂SO₄) and evaporated invacuo. The residue was purified by flash chromatography (silica), eluent1% MeOH, 99% CHCl₃ to give a pale yellow solid identified as2-(3,3-difluoro-pyrrolidin-1-yl)-pyrimidine-5-carboxylic acid ethylester (1.4 g, 5.44 mmol, 68% yield).

[MH]⁺=258.2

B. [2-(3,3-Difluoro-pyrrolidin-1-yl)-pyrimidin-5-yl]-methanol

2-(3,3-Difluoro-pyrrolidin-1-yl)-pyrimidine-5-carboxylic acid ethylester (1.4 g, 5.44 mmol) was dissolved in toluene (50 mL). This solutionwas cooled to −78° C. under nitrogen and DIBAL (1M solution in toluene)(16.33 mL, 16.33 mmol) was added dropwise. After 90 mins at thistemperature the reaction was allowed to warm to rt and stirred for 2hrs. The reaction mixture was cooled to 0° C. and 2M HCl was addeddropwise followed by iced water (50 mL). The precipitate was filteredoff through Celite and the filtrate basified to pH9 with sodiumcarbonate. The organic layer was separated and the aqueous layerextracted with EtOAc (3×100 mL). The combined organic extracts werewashed with water (1×30 mL), bine (1×30 mL), dried (Na₂SO₄) andevaporated in vacuo. The residue was purified by flash chromatography(silica), eluent 4% MeOH, 96% CHCl₃ to give a white solid identified as[2-(3,3-difluoro-pyrrolidin-1-yl)-pyrimidin-5-yl]-methanol (650 mg, 3.02mmol, 55% yield).

[MH]⁺=216.3

C. Acetic acid 2-(3,3-difluoro-pyrrolidin-1-yl)-pyrimidin-5-ylmethylester

[2-(3,3-Difluoro-pyrrolidin-1-yl)-pyrimidin-5-yl]-methanol (650 mg, 3.02mmol) was dissolved in DCM (50 mL). This solution was cooled to 0° C.,acetic anhydride (463 mg, 4.53 mmol), 4-(dimethylamino)pyridine (185 mg,1.51 mmol) and pyridine (1.2 g, 15.1 mmol) were added. The reactionmixture was allowed to reach rt and stirred at rt for 2 hrs after whichtime the reaction mixture was diluted with CHCl₃ (50 mL), washed withwater (1×30 mL), brine (1×30 mL), dried (Na₂SO₄) and evaporated invacuo. The residue was pureed by flash chromatography (silica) eluent80% Pet. Ether, 20% EtOAc to give a white solid identified as aceticacid 2-(3,3-difluoro-pyrrolidin-1-yl)-pyrimidin-5-ylmethyl ester (737mg, 2.87 mmol, 95% yield).

[MH]⁺=258.2

D.2-[2-(3,3-Difluoro-pyrrolidin-1-yl)-pyrimidin-5-ylmethyl]-5-methoxymethyl-1H-pyrazole-4-carboxylicacid methyl ester

Acetic acid 2-(3,3-difluoro-pyrrolidin-1-yl)-pyrimidin-5-ylmethyl ester(695 mg, 2.7 mmol) was dissolved in dry acetonitrile (50 mL). To thissolution was added methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate(CAS no. 318496-66-1 (synthesised according to the method described inWO 2012/009009)) (460 mg, 2.7 mmol) and trimethylsilyl triflate (1.076mL, 5.95 mmol). The reaction mixture was stirred at 80° C. for 18 hrsafter which time the solvent was removed in vacuo and the residue takenup in EtOAc (50 mL), washed with water (1×30 mL), brine (1×30 mL), dried(Na₂SO₄) and evaporated in vacuo. The residue was purified by flashchromatography (silica), eluent gradient from 30% Pet Ether, 70% EtOActo 100% EtOAc to afford two isomeric products. The faster runningproduct was identified as the undesired regioisomer. The slower runningproduct afforded a yellow oil and was identified as2-[2-(3,3-difluoro-pyrrolidin-1-yl)-pyrimidin-5-ylmethyl]-5-methoxymethyl-1H-pyrazole-4-carboxylicacid methyl ester (210 mg, 0.57 mmol, 21% yield).

[MH]⁺=368.3

E.1-[2-(3,3-Difluoro-pyrrolidin-1-yl)-pyrimidin-5-ylmethyl]-3-methoxymethyl-1H-pyrazole-4-carboxylicAcid

2-[2-(3,3-Difluoro-pyrrolidin-1-yl)-pyrimidin-5-ylmethyl]-5-methoxymethyl-1H-pyrazole-4-carboxylicacid methyl ester (210 mg, 0.57 mmol) was dissolved in THF (50 mL) andwater (5 mL). Lithium hydroxide (68 mg, 2.86 mmol) was added. Thereaction mixture was stirred at room temperature for 18 hrs after whichtime the reaction mixture was concentrated in vacuo and the residue wasacidified with 1M HCl to pH2 and extracted CHCl₃ (3×50 mL). The combinedextracts were washed with water (1×30 mL), brine (1×30 mL), dried(Na₂SO₄) and evaporated in vacuo to give a white solid identified as1-[2-(3,3-difluoro-pyrrolidin-1-yl)-pyrimidin-5-ylmethyl]-3-methoxymethyl-1H-pyrazole-4-carboxylicacid (130 mg, 0.37 mmol, 64% yield).

[MH]⁺=354.2

F.1-{[2-(3,3-Difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide

1-[2-(3,3-Difluoro-pyrrolidin-1-yl)-pyrimidin-5-ylmethyl]-3-methoxymethyl-1H-pyrazole-4-carboxylicacid (130 mg, 0.37 mmol) was dissolved in DCM (30 mL).(2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (167 mg, 0.44 mmol) and N,N-diisopropylethyamine(143 mg, 1.1 mmol) were added at rt. After 20 min2-fluoro-3-methoxy-6-tetrazol-1-yl-benzylamine (90 mg, 0.40 mmol) wasadded and the reaction mixture stirred at rt for 18 hrs. The reactionmixture was diluted with CHCl₃ (50 mL) and washed with sat NaHCO₃ (aq)(1×30 mL), water (1×30 mL), brine (1×30 mL), dried (Na₂SO₄) andevaporated in vacuo to give a yellow oil. The residue was purified byflash chromatography (silica), eluent 4% MeOH, 96% CHCl₃ to give a whitesolid identified as1-{[2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide(112 mg, 0.2 mmol, 55% yield).

[MH]⁺=559.3

¹H NMR (d6-DMSO) δ: 2.50-2.57 (2H, m), 3.18 (3H, s), 3.69 (2H, t, J=7.4Hz), 3.87 (2H, t, J=12.2 Hz), 3.94 (3H, s), 4.22 (2H, d, J=4.7 Hz), 4.41(2H, s), 5.15 (2H, s), 7.37-7.41 (2H, m), 8.09 (1H, s), 8.14 (1H, t,J=5.2 Hz), 8.41 (2H, s), 9.73 (1H, s)

Example 79N-{[2-Fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide

A.N-{[2-Fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide

3-Methoxymethyl-1-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-1H-pyrazole-4-carboxylicacid (CAS no. 1938129-73-7 (synthesised according to the methoddescribed in WO 2016083816)) (200 mg, 0.63 mmol) was dissolved in DCM(30 mL). (2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (287 mg, 0.76 mmol) and N,N-diisopropylethyamine(244 mg, 1.89 mmol) were added at rt. After 20 min2-fluoro-3-methoxy-6-tetrazol-1-yl-benzylamine (143 mg, 0.64 mmol) wasadded and the reaction mixture stirred at rt for 18 hrs. The reactionmixture was diluted with CHCl₃ (50 mL) and washed with sat NaHCO₃ (aq)(1×30 mL), water (1×30 mL), brine (1×30 mL), dried (Na₂SO₄) andevaporated in vacuo to give a yellow oil. The residue was purified byflash chromatography (silica), eluent 4% MeOH, 96% CHCl₃ to give a whitesolid identified asN-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide(230 mg, 0.44 mmol, 70% yield).

[MH]⁺=523.4

¹H NMR (d6-DMSO) δ: 1.89-1.92 (4H, m), 3.18 (3H, s), 3.45 (4H, t, J=6.7Hz), 3.93 (3H, s), 4.21 (2H, d, J=4.6 Hz), 4.42 (2H, s), 5.10 (2H, s),7.33-7.41 (2H, m), 8.07 (1H, s), 8.15 (1H, t, J=4.9 Hz), 8.33 (2H, s),9.73 (1H, s)

TABLE 1

Exam- Free ple Base number R14 R15 R18 U MW [M + H]⁺ 1 F MeO absent N478.5 479.3

TABLE 2

Exam- ple Free Base number R5 Q R15 L K J MW [M + H]⁺ 2 CH₂OMe C—F MeOCH N N 492.5 3 CH₂OMe C—H MeO CH N N 474.5 4 CH₂OMe C—H MeO N CH N 474.5475.3 5 NH₂ C—F MeO CH CH N 462.5 463.3 6 CF₃ C—F MeO CH CH N 515.5516.3 7 NMe₂ C—F MeO CH CH N 490.5 491.4 8 CH₂OMe C—H MeO N CH C—CN498.5 499.3 9 CH₂OMe C—F MeO N CH C—CN 516.5 10  CH₂OMe N MeO CH CH N474.5 475.3

TABLE 3

Example Free Base number T R14 R15 R16 R17 MW [M + H]⁺ 11 H Me OMe Me H501.6 502.4 12 H CN OMe H H 498.5 13 H CN H H H 468.5 469.3 14 H CHF₂OMe H H 523.5 15 H H OMe Cl H 508.0 16 H CN H Cl H 503.0 525.3 [M + Na]⁺17 H F H Cl H 495.9 496.3 18 H F Cl H H 495.9 19 H F H Me H 475.5 20 H HOMe Me H 487.6 488.3 21 H CN H Me H 482.5 22 H Me OMe H H 487.6 488.3 23H CN H H OMe 498.5 24 H F OMe H CHF₂ 541.5 25 H F OMe CHF₂ H 541.5 26 HF H F H 479.5 480.3 27 H F H H Me 475.5 476.3 28 H F Me H H 475.5 476.329 H Cl Me H H 492.0 492.3 30 F F OMe H H 509.5 510.3

TABLE 4

Example number R14 R15 Free Base MW [M + H]⁺ 31 H OMe 476.5 477.4 32 ClOMe 511.0 33 Me OMe 490.6 34 Cl H 480.9 481.2

TABLE 5

Example Free Base number R5 R14 R15 R16 R17 R18 MW [M + H]⁺ 35 NH₂ F OMeH H F 479.5 480.3 36 CH₂OMe F OMe H OMe F 538.5 37 CH₂OMe CN H H OMe H497.5 498.3 38 CH₂OMe CN OMe H H H 497.5 498.3 39 CH₂OMe F OMe H H

558.6 559.4 40 CH₂OMe H OMe H H

540.6 541.4 41 CH₂OMe H OMe H H Me 486.6 487.4 42 CH₂OMe F OMe H H CONH₂533.6 534.4 43 NH₂ F OMe H H CN 486.5 487.3 44 NMe₂ F OMe H H CN 514.6515.4 45 NH₂ H OMe H H CN 468.5 46 NMe₂ H OMe H H CN 496.6 47 NH₂ H OMeH H CF₃ 511.5 48 NH₂ H OMe H H CHF₂ 493.5 49 CH₂OMe H F H H

528.5 529.3 50 NMe₂ F OMe H H F 507.5

TABLE 6

Exam- ple Free Base number A R5 R14 MW [M + H]⁺ 51

CH₂OMe F 516.5 517.3 52

CH₂OMe F 516.5 517.3 53

CH₂OMe F 533.5 534.3 54

CH₂OMe H 498.5 55

CH₂OMe H 498.5 56

CH₂OMe H 515.5 57

CH₂OMe F 519.6 520.2

TABLE 7

Example Free Base number V R5 R18 MW [M + H]⁺ 58 N CH₂OMe CN 479.5 480.359 N CF₃ CN 503.5

TABLE 1a

Example Free Base number R14 R15 R18 U MW [M + H]⁺ 60 F MeO

C 545.6 546.4 61 H MeO

C 527.6 528.4 62 F H

C 515.5

TABLE 5a

Exam- ple Free Base number R5 R14 R15 R16 R17 R18 MW [M + H]⁺ 63 CF₃

H H OMe H 564.5 64 CF₃

H H H F 552.5 553.3 65 NH₂

H H OMe F 529.5 66 NH₂

H H OMe H 511.5 67 NH₂

H H H F 499.5 68 NMe₂

H H OMe F 557.6 69 NMe₂

H H OMe H 539.6 70 NMe₂

H H H F 527.6 71 NH₂

H H Cl H 516.0 516.3 72 CH₂OMe

H H Cl H 545.0 545.3 73 CH₂OMe

H H H Cl 545.0 545.3 74 CH₂OMe

H H H H 510.6 511.3 75 CH₂OMe

H H H Me 524.6 76 CH₂OMe CN H H H F 485.5

TABLE 7a

Free Example Base number V R5 R14 R15 R18 MW [M + H]⁺ 77 CH CH₂OMe F OMe

521.5 522.4 78 CH CH₂OMe H OMe

503.6 79 N CH₂OMe F OMe

522.5 523.4 80 N CH₂OMe H OMe

504.5 505.4 81 CH CH₂OMe F H

491.5 82 N CH₂OMe F H

492.5 83 CH CF₃ F OMe

545.5 546.1 84 CH CF₃ H OMe

527.5 85 CH CF₃ F H

515.5

TABLE 7b

Example Free Base number V R5 R14 R18 MW [M + H]⁺ 86 N CH₂OMe F

558.5 559.3 87 CH CH₂OMe F

557.5 558.1 88 N CH₂OMe H

540.5 541.2 89 CH CH₂OMe H

539.5

TABLE 8 Compound names Example Number Name 1N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 2N-[(4-fluoro-5-methoxypyridazin-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 33-(methoxymethyl)-N-[(5-methoxypyridazin-3-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 43-(methoxymethyl)-N-[(6-methoxypyrimidin-4-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 53-amino-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 6N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide 73-(dimethylamino)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 8N-[(5-cyano-2-methoxypyridin-4-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 9N-[(5-cyano-3-fluoro-2-methoxypyridin-4-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 103-(methoxymethyl)-N-[(4-methoxypyrimidin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 11N-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 12N-[(3-cyano-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 13N-[(3-cyanopyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 14N-{[3-(difluoromethyl)-4-methoxypyridin-2-yl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 15N-[(5-chloro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 16N-[(5-chloro-3-cyanopyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 17N-[(5-chloro-3-fluoropyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 18N-[(4-chloro-3-fluoropyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 19N-[(3-fluoro-5-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 20N-[(4-methoxy-5-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 21N-[(3-cyano-5-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 22N-[(4-methoxy-3-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 23N-[(3-cyano-6-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 24N-{[6-(difluoromethyl)-3-fluoro-4-methoxypyridin-2-yl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 25N-{[5-(difluoromethyl)-3-fluoro-4-methoxypyridin-2-yl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 26N-[(3,5-difluoropyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 27N-[(3-fluoro-6-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 28N-[(3-fluoro-4-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 29N-[(3-chloro-4-methylpyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 301-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide 31N-[(5-methoxy-1-methylpyrazol-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 32N-[(4-chloro-5-methoxy-1-methylpyrazol-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 33N-[(5-methoxy-1,4-dimethylpyrazol-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 34N-[(4-chloro-1-methylpyrazol-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 353-amino-N-[(2,6-difluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 36N-[(2,6-difluoro-3,5-dimethoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 37N-[(2-cyano-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 38N-[(2-cyano-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 39N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 40N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 41N-[(5-methoxy-2-methylphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 42N-[(6-carbamoyl-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 433-amino-N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 44N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(dimethylamino)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 453-amino-N-[(2-cyano-5-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 46N-[(2-cyano-5-methoxyphenyl)methyl]-3-(dimethylamino)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 473-amino-N-{[5-methoxy-2-(trifluoromethyl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 483-amino-N-{[2-(difluoromethyl)-5-methoxyphenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 49N-{[5-fluoro-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 50N-[(2,6-difluoro-3-methoxyphenyl)methyl]-3-(dimethylamino)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 51N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({5-[(2-oxopyridin-1-yl)methyl]pyridin-2-yl}methyl)pyrazole-4-carboxamide 52N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({6-[(2-oxopyridin-1-yl)methyl]pyridin-3-yl}methyl)pyrazole-4-carboxamide 53N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide 54N-[(2-cyano-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({5-[(2-oxopyridin-1-yl)methyl]pyridin-2-yl}methyl)pyrazole-4-carboxamide 55N-[(2-cyano-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({6-[(2-oxopyridin-1-yl)methyl]pyridin-3-yl}methyl)pyrazole-4-carboxamide 56N-[(2-cyano-5-methoxyphenyl)methyl]-1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide 57N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopiperidin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 58N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide 59N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide 60N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide61N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 62N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 63N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide 64N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide 653-amino-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 663-amino-N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 673-amino-N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 683-(dimethylamino)-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 693-(dimethylamino)-N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 703-(dimethylamino)-N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 713-amino-N-{[5-chloro-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 72N-{[5-chloro-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 73N-{[2-chloro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 743-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-{[2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}pyrazole-4-carboxamide 753-(methoxymethyl)-N-{[2-methyl-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 76N-[(2-cyano-6-fluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 77N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide 78N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide 79N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide 80N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide 81N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide 82N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide 83N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide 84N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide 85N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide 861-{[2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide871-{[6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]methyl}-N-{[2-fluoro-3-methoxy-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide881-{[2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}-N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide 891-{[6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]methyl}-N-{[5-methoxy-2-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide

TABLE 9 NMR data of examples (solvent d6 DMSO) Example Number Chemicalshift Reference 3.20 (3H, s), 3.71 (6H, s), 4.32 (2H, d, J = 5.8 Hz),4.53 (2H, s), 5.07 (2H, s), Example A 5.28 (2H, s), 6.22 (1H, td, J =6.7, 1.4 Hz), 6.37 (1H, t, J = 2.3 Hz), 6.40 (1H, dd, J = 9.2, 1.4 Hz),6.44 (2H, d, J = 2.3 Hz), 7.20-7.29 (4H, m), 7.41 (1H, ddd, J = 9.1,6.6, 2.1 Hz), 7.76 (1H, dd, J = 6.8, 2.1 Hz), 8.24 (1H, s), 8.32 (1H, t,J = 5.9 Hz). Reference 3.82 (3H, s), 4.36 (2H, d, J = 5.7 Hz), 5.04 (2H,s), 5.07 (2H, s), 5.38 (2H, s), Example B 6.21-6.24 (1H, m), 6.39 (1H,t, J = 0.7 Hz), 6.86-6.87 (1H, m), 7.04-7.07 (2H, m), 7.20 (2H, d, J =8.1 Hz), 7.26 (2H, d, J = 8.1 Hz), 7.39-7.43 (1H, m), 7.76 (1H, dd, J =6.6, 1.6 Hz), 8.00 (1H, s), 8.27 (1H, t, J = 5.9 Hz). Reference 3.82(3H, s), 4.41 (2H, d, J = 5.8 Hz), 4.54 (2H, s), 5.57 (2H, s), 6.87-6.91(1H, m), Example C 7.03-7.09 (2H, m), 7.67 (1H, dd, J = 8.8, 2.1 Hz),8.07 (1H, d, J = 8.8 Hz), 8.10 (1H, d, J = 1.9 Hz), 8.30 (1H, d, J = 1.7Hz), 8.37 (1H, s), 8.39 (1H, t, J = 5.8 Hz), 8.92 (1H, d, J = 2.2 Hz)Reference 3.25 (3H, s), 3.92 (3H, s), 4.46-4.57 (4H, m), 5.07 (2H, s),5.28 (2H, s), 6.22 (1H, Example D td, J = 1.4, 6.7 Hz), 6.39 (1H, ddd, J= 0.7, 1.4, 9.2 Hz), 7.17-7.28 (5H, m), 7.41 (1H, ddd, J = 2.1, 6.6, 8.9Hz), 7.75 (1H, ddd, J = 0.7, 2.1, 6.8 Hz), 8.21-8.29 (2H, m), 8.42 (1H,t, J = 5.4 Hz) Reference 3.21 (3H, s), 3.92 (3H, s), 4.47-4.55 (4H, m),5.06 (2H, s), 5.27 (2H, s), 6.21 (1H, Example E td, J = 6.7, 1.4 Hz),6.39 (1H, d, J = 9.1 Hz), 7.17-7.31 (5H, m), 7.40 (1H, ddd, J = 8.9,6.6, 2.1 Hz), 7.67 (1H, dd, J = 8.6, 1.5 Hz), 7.75 (1H, dd, J = 6.8, 2.1Hz), 8.20 (1H, s), 8.40 (1H, t, J = 5.2 Hz) Reference 3.12 (3H, s), 3.83(3H, s), 4.43 (2H, s), 4.52-4.59 (2H, m), 5.05 (2H, s), 5.25 (2H, s),Example F 6.21 (1H, td, J = 1.4, 6.7 Hz), 6.39 (1H, dt, J = 1.0, 9.2Hz), 7.15-7.44 (8H, m), 7.75 (1H, ddd, J = 0.7, 2.1, 6.8 Hz), 8.08 (1H,t, J = 4.9 Hz), 8.22 (1H, s) Reference 1.90-1.94 (4H, m), 3.31-3.37 (4H,m), 3.82 (3H, s), 4.39 (2H, d, J = 5.6 Hz), Example G 5.26 (2H, s), 6.44(1H, d, J = 8.6 Hz), 6.85-6.90 (1H, m), 7.03-7.10 (2H, m), 7.50 (1H, dd,J = 8.8, 2.4 Hz), 8.14 (1H, d, J = 2.3 Hz), 8.36 (1H, d, J = 0.6 Hz),8.74 (1H, t, J = 5.8 Hz) 1 1.98 (3H, s), 3.31 (3H, s), 3.92 (3H, s),4.51 (2H, s), 4.53 (2H, dd, J = 5.4, 2.0 Hz), 5.21 (2H, s), 5.28 (2H,s), 7.16-7.23 (6H, m), 7.52 (1H, s), 8.23 (1H, s), 8.25 (1H, d, J = 3.1Hz), 8.42 (1H, t, J = 5.2 Hz) 4 3.24 (3H, s), 3.90 (3H, s), 4.39 (2H, d,J = 5.8 Hz), 4.54 (2H, s), 5.07 (2H, s), 5.30 (2H, s), 6.22 (1H, dt, J =6.8, 1.4 Hz), 6.39 (1H, d, J = 8.8 Hz), 6.76 (1H, d, J = 0.7 Hz), 7.25(2H, d, J = 8.5 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.39-7.43 (1H, m), 7.76(1H, dd, J = 6.7, 2.2 Hz), 8.28 (1H, s), 8.51 (1H, t, J = 5.8 Hz), 8.72(1H, d, J = 0.9 Hz) 5 3.91 (3H, s), 4.46 (2H, dd, J = 5.6, 2.0 Hz), 5.03(2H, s), 5.06 (2H, s), 5.34 (2H, s, br), 6.20-6.24 (1H, m), 6.39 (1H, d,J = 8.8 Hz), 7.15-7.18 (1H, m), 7.19 (2H, d, J = 8.2 Hz), 7.26 (2H, d, J= 8.2 Hz), 7.38-7.43 (1H, m), 7.75 (1H, dd, J = 6.8, 2.0 Hz), 8.01 (1H,s), 8.21 (1H, d, J = 5.5 Hz), 8.23 (1H, s) 6 3.92 (3H, s), 4.49 (2H, dd,J = 5.6, 2.0 Hz), 5.08 (2H, s), 5.40 (2H, s), 6.21-6.24 (1H, m), 6.40(1H, d, J = 9.0 Hz), 7.16-7.25 (1H, m), 7.29 (4H, s), 7.39-7.43 (1H, m),7.76 (1H, dd, J = 6.8, 2.0 Hz), 8.21 (1H, d, J = 5.5 Hz), 8.44 (1H, s),8.70 (1H, t, J = 5.4 Hz) 7 2.69 (6H, s), 3.92 (3H, s), 4.53 (2H, dd, J =5.9, 2.0 Hz), 5.07 (2H, s), 5.15 (2H, s), 6.20-6.24 (1H, m), 6.40 (1H,d, J = 8.9 Hz), 7.16-7.28 (4H, m), 7.39-7.43 (1H, m), 7.76 (1H, dd, J =6.9, 1.9 Hz), 8.04 (2H, s), 8.23 (1H, d, J = 5.5 Hz), 8.32 (1H, t, J =5.4 Hz) 8 3.23 (3H, s), 3.92 (3H, s), 4.49 (2H, d, J = 5.6 Hz), 4.55(2H, s), 5.08 (2H, s), 5.31 (2H, s), 6.21-6.25 (1H, m), 6.40 (1H, d, J =9.6 Hz), 6.84 (1H, s), 7.22-7.32 (4H, m), 7.39-7.43 (1H, m), 7.76 (1H,dd, J = 6.8, 1.9 Hz), 8.28 (1H, s), 8.58 (1H, t, J = 5.7 Hz) 8.66 (1H,s) 10 3.26 (3H, s), 3.89 (3H, s), 4.50 (2H, d, J = 5.6 Hz), 4.54 (2H,s), 5.07 (2H, s), 5.30 (2H, s), 6.20-6.24 (1H, m), 6.40 (1H, d, J = 8.8Hz), 6.81 (1H, d, J = 5.7 Hz), 7.23-7.28 (4H, m), 7.39-7.43 (1H, m),7.76 (1H, dd, J = 6.5, 1.9 Hz), 8.27 (1H, s), 8.41-8.47 (2H, m) 11 2.28(3H, s), 2.34 (3H, s), 3.24 (3H, s), 3.95 (3H, s), 4.52 (2H, s), 4.59(2H, d, J = 5.2 Hz), 5.07 (2H, s), 5.30 (2H, s), 6.21-6.25 (1H, m), 6.39(1H, d, J = 8.8 Hz), 7.24-7.29 (4H, m), 7.39-7.44 (1H, m), 7.77 (1H, dd,J = 6.7, 1.9 Hz), 8.26 (1H, s), 8.24 (1H, s), 8.60 (1H, t, J = 5.0 Hz)13 3.31 (3H, s), 4.52 (2H, s), 4.70 (2H, d, J = 5.4 Hz), 5.07 (2H, s),5.29 (2H, s), 6.22 (1H, td, J = 6.6, 1.3 Hz), 6.39 (1H, d, J = 8.9 Hz),7.22-7.29 (4H, m), 7.38-7.43 (1H, m), 7.51 (1H, dd, J = 7.9, 4.9 Hz),7.76 (1H, dd, J = 6.8, 1.9 Hz), 8.26 (1H, s), 8.30 (1H, dd, J = 7.9, 1.6Hz), 8.62 (1H, t, J = 5.2 Hz), 8.79 (1H, dd, J = 4.9, 1.6 Hz) 16 3.25(3H, s), 4.52 (2H, s), 4.66 (2H, d, J = 5.4 Hz), 5.07 (2H, s), 5.29 (2H,s), 6.22 (1H, td, J = 6.6, 1.3 Hz), 6.40 (1H, d, J = 8.9 Hz), 7.22-7.28(4H, m), 7.39-7.43 (1H, m), 7.76 (1H, dd, J = 6.6, 1.9 Hz), 8.25 (1H,s), 8.59 (1H, d, J = 2.4 Hz), 8.64 (1H, t, J = 5.3 Hz), 8.87 (1H, d, J =2.4 Hz) 17 3.25 (3H, s), 4.48-4.56 (4H, m), 5.07 (2H, s), 5.28 (2H, s),6.20-6.24 (1H, m), 6.40 (1H, d, J = 9.0 Hz), 7.21-7.28 (4H, m),7.39-7.43 (1H, m), 7.75 (1H, dd, J = 6.6, 1.9 Hz), 8.07 (1H, dd, J =9.8, 1.9 Hz), 8.25 (1H, s), 8.46-8.56 (2H, m) 20 2.20 (3H, s), 3.22 (3H,s), 4.05 (3H, s), 4.55 (2H, s), 4.63 (2H, d, J = 5.5 Hz), 5.07 (2H, s),5.32 (2H, s), 6.23 (1H, dt, J = 6.6, 1.3 Hz), 6.39 (1H, d, J = 8.9 Hz),7.25-7.29 (4H, m), 7.41 (1H, ddd, J = 8.8, 6.6, 2.1 Hz), 7.45 (1H, brs), 7.78 (1H, dd, J = 6.6, 1.9 Hz), 8.27 (1H, s), 8.46 (1H, s), 8.65(1H, t, J = 5.5 Hz) 22 2.11 (3H, s), 3.27 (3H, s), 3.85 (3H, s), 4.49(2H, d, J = 4.9 Hz), 4.50 (2H, s), 5.06 (2H, s), 5.27 (2H, s), 6.20-6.23(1H, m), 6.39 (1H, d, J = 9.0 Hz), 6.96 (1H, d, J = 5.7 Hz), 7.22-7.27(4H, m), 7.38-7.43 (1H, m), 7.75 (1H, dd, J = 6.6, 2.0 Hz), 8.27-8.29(2H, m), 8.43 (1H, t, J = 4.8 Hz) 26 3.25 (3H, s), 4.51 (2H, s), 4.55(2H, d, J = 5.2 Hz), 5.07 (2H, s), 5.28 (2H, s), 6.20-6.24 (1H, m),6.38-6.41 (1H, m), 7.21-7.28 (4H, m), 7.38-7.43 (1H, m), 7.75 (1H, dd, J= 6.7, 2.0 Hz), 7.90-7.96 (1H, m), 8.25 (1H, s), 8.44-8.47 (2H, m) 272.44 (3H, s), 3.24 (3H, s), 4.52-4.54 (4H, m), 5.07 (2H, s), 5.28 (2H,s), 6.20-6.24 (1H, m), 6.39 (1H, d, J = 8.8 Hz), 7.19-7.27 (5H, m),7.38-7.43 (1H, m), 7.55-7.60 (1H, m), 7.76 (1H, dd, J = 8.6, 1.9 Hz),8.25 (1H, s), 8.40 (1H, t, J = 5.3 Hz) 28 2.28 (3H, d, J = 1.0 Hz), 3.26(3H, s), 4.51 (2H, s), 4.56 (2H, dd, J = 5.0, 1.2 Hz), 5.07 (2H, s),5.28 (2H, s), 6.20-6.24 (1H, m), 6.39 (1H, d, J = 9.0 Hz), 7.22-7.30(5H, m), 7.38-7.43 (1H, m), 7.76 (1H, dd, J = 6.7, 1.9 Hz), 8.23 (1H, d,J = 4.8 Hz), 8.27 (1H, s), 8.44 (1H, t, J = 5.2 Hz) 29 2.38 (3H, s),3.29 (3H, s), 4.49 (2H, d, J = 1.8 Hz), 4.62 (2H, d, J = 5.1 Hz), 5.07(2H, s), 5.29 (2H, s), 6.20-6.24 (1H, m), 6.39 (1H, d, J = 9.2 Hz), 7.24(2H, d, J = 8.5 Hz), 7.26 (2H, d, J = 8.5 Hz), 7.35 (1H, d, J = 4.9 Hz),7.38-7.45 (1H, m), 7.76 (1H, dd, J = 6.8, 1.9 Hz), 8.29 (1H, s), 8.36(1H, d, J = 4.8 Hz), 8.48 (1H, t, J = 5.1 Hz) 30 3.25 (3H, s), 3.92 (3H,s), 4.50 (2H s), 4.53 (2H, dd, J = 5.3, 2.0 Hz), 5.01 (2H, s), 5.28 (2H,s), 6.43 (1H, dd, J = 10.0, 5.4 Hz), 7.19 (1H, t, J = 6.0 Hz), 7.23 (2H,d, J = 8.2 Hz), 7.29 (2H, d, J = 8.2 Hz), 7.54-7.59 (1H, m), 8.02 (1H,t, J = 3.9 Hz), 8.24 (1H, d, J = 5.5 Hz), 8.26 (1H, s), 8.42 (1H, t, J =5.3 Hz) 31 3.23 (3H, s), 3.48 (3H, s), 3.81 (3H, s), 4.20 (2H, d, J =5.5 Hz), 4.52 (2H, s), 5.07 (2H, s), 5.27 (2H, s), 5.55 (1H, s), 6.22(1H, dt, J = 6.8, 1.4 Hz), 6.39 (1H, d, J = 8.8 Hz), 7.23 (2H, d, J =8.3 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.41 (1H, ddd, J = 8.9, 6.7, 2.2 Hz),7.75 (1H, dd, J = 6.8, 2.1 Hz), 8.19 (1H, t, J = 5.5 Hz), 8.23 (1H, s)34 3.22 (3H, s), 3.77 (3H, s), 4.33 (2H, d, J = 5.7 Hz), 4.50 (2H, s),5.06 (2H, s), 5.27 (2H, s), 6.19-6.24 (1H, m), 6.39 (1H, d, J = 9.0 Hz),7.21-7.27 (4H, m), 7.38-7.43 (1H, m), 7.76 (1H, dd, J = 6.7, 1.9 Hz),7.89 (1H, s), 8.18 (1H, t, J = 5.2 Hz), 8.24 (1H, s) 35 3.81 (3H, s),4.38 (2H, d, J = 5.0 Hz), 5.01 (2H, s), 5.06 (2H, s), 5.37 (2H, br.s),6.22 (1H, td, J = 6.7, 1.3 Hz), 6.39 (1H, d, J = 8.9 Hz), 7.00 (1H, td,J = 9.2, 1.7 Hz), 7.11 (1H, td, J = 9.3, 5.5 Hz), 7.17 (2H, d, J = 8.2Hz), 7.25 (2H, d, J = 8.2 Hz), 7.38-7.43 (1H, m), 7.76 (1H, dd, J = 6.7,2.0 Hz), 7.97 (1H, s), 8.10 (1H, t, J = 5.2 Hz) 37 3.22 (3H, s), 3.91(3H, s), 4.34 (2H, d, J = 5.7 Hz), 4.53 (2H, s), 5.07 (2H, s), 5.29 (2H,s), 6.20-6.24 (1H, m), 6.39 (1H, d, J = 9.2 Hz), 7.18 (1H, d, J = 8.6Hz), 7.23 (2H, d, J = 8.4 Hz), 7.26 (2H, d, J = 8.4 Hz), 7.38-7.43 (1H,m), 7.56 (1H, d, J = 1.9 Hz), 7.74 (1H, s), 7.75 (1H, d, J = 6.6 Hz),8.26 (1H, s), 8.27 (1H, t, J = 5.8 Hz) 38 3.21 (3H, s), 3.91 (3H, s),4.50 (2H, d, J = 5.6 Hz), 4.53 (2H, s), 5.07 (2H, s), 5.29 (2H, s),6.20-6.24 (1H, m), 6.40 (1H, d, J = 8.8 Hz), 7.04 (1H, d, J = 7.6 Hz),7.13 (1H, d, J = 8.2 Hz), 7.23-7.28 (4H, m), 7.39-7.43 (1H, m), 7.60(1H, t, J = 8.1 Hz), 7.76 (1H, dd, J = 6.8, 1.9 Hz), 8.26 (1H, s), 8.50(1H, t, J = 5.6 Hz) 39 3.18 (3H, s), 3.94 (3H, s), 4.22 (2H, d, J = 4.8Hz), 4.41 (2H, s), 5.06 (2H, s), 5.24 (2H, s), 6.20-6.23 (1H, m), 6.39(1H, d, J = 9.0 Hz), 7.19 (2H, d, J = 8.2 Hz), 7.24 (2H, d, J = 8.2 Hz),7.33-7.43 (3H, m), 7.75 (1H, dd, J = 6.8, 1.9 Hz), 8.11 (1H, s), 8.15(1H, t, J = 5.2 Hz), 9.73 (1H, s) 40 3.19 (3H, s), 3.82 (3H, s), 4.16(2H, d, J = 5.7 Hz), 4.49 (2H, s), 5.07 (2H, s), 5.28 (2H, s), 6.22 (1H,t, J = 5.3 Hz), 6.39 (1H, d, J = 8.8 Hz), 7.06-7.11 (2H, m), 7.22 (2H,d, J = 8.4 Hz), 7.26 (2H, d, J = 8.2 Hz), 7.38-7.43 (1H, m), 7.48 (1H,d, J = 8.6 Hz), 7.76 (1H, dd, J = 6.8, 2.0 Hz), 8.19 (1H, s), 8.27 (1H,t, J = 5.6 Hz), 9.76 (1H, s) 41 2.20 (3H, s), 3.17 (3H, s), 3.68 (3H,s), 4.32 (2H, d, J = 5.5 Hz), 4.52 (2H, s), 5.07 (2H, s), 5.28 (2H, s),6.20-6.24 (1H, m), 6.39 (1H, d, J = 9.6 Hz), 6.73 (1H, q, J = 2.8 Hz),6.80 (1H, d, J = 2.6 Hz), 7.09 (1H, d, J = 8.3 Hz), 7.25 (4H, q, J = 8.3Hz), 7.38-7.43 (1H, m), 7.75 (1H, d, J = 1.8 Hz), 8.18 (1H, t, J = 5.6Hz), 8.25 (1H, s) 42 3.21 (3H, s), 3.92 (3H, s), 4.51-4.52 (4H, m), 5.06(2H, s), 5.27 (2H, s), 6.18-6.22 (1H, m), 6.39 (1H, d, J = 8.8 Hz),7.20-7.30 (7H, m), 7.35-7.45 (1H, m), 7.66 (1H, dd, J = 8.7, 1.3 Hz),7.75 (1H, dd, J = 6.7, 1.9 Hz), 8.20 (1H, s), 8.39 (1H, t, J = 5.1 Hz)43 3.92 (3H, s), 4.50 (2H, d, J = 4.7 Hz), 5.07 (2H, s), 5.11 (2H, s),6.03 (2H, s), 6.21-6.25 (1H, m), 6.41 (1H, d, J = 8.9 Hz), 7.20-7.31(5H, m), 7.39-7.44 (1H, m), 7.66 (1H, dd, J = 8.6, 1.2 Hz), 7.76 (1H,dd, J = 6.6, 1.9 Hz), 8.09 (1H, s), 8.46 (1H, t, J = 5.0 Hz) 44 2.73(6H, s), 3.92 (3H, s), 4.53 (2H, d, J = 5.1 Hz), 5.06 (2H, s), 5.15 (2H,s), 6.21-6.24 (1H, m), 6.40 (1H, d, J = 9.1 Hz), 7.19-7.29 (5H, m),7.38-7.43 (1H, m), 7.67 (1H, d, J = 8.6 Hz), 7.76 (1H, dd, J = 6.7, 1.8Hz), 8.04 (1H, s), 8.39 (1H, t, J = 4.9 Hz) 49 3.20 (3H, s), 4.20 (2H,d, J = 5.7 Hz), 4.49 (2H, s), 5.07 (2H, s), 5.28 (2H, s), 6.22 (1H, dt,J = 6.6, 1.4 Hz), 6.39 (1H, d, J = 9.0 Hz), 7.23 (2H, d, J = 8.4 Hz),7.27 (2H, d, J = 8.3 Hz), 7.39-7.43 (3H, m), 7.65-7.68 (1H, m), 7.76(1H, dd, J = 6.5, 1.9 Hz), 8.20 (1H, s), 8.35 (1H, t, J = 5.7 Hz), 9.85(1H, s) 51 3.21 (3H, s), 3.92 (3H, s), 4.50 (2H, s), 4.53 (2H, d, J =4.8 Hz), 5.09 (2H, s), 5.38 (2H, s), 6.24 (1H, td, J = 6.7, 1.3 Hz),6.39 (1H, d, J = 8.8 Hz), 7.14 (1H, d, J = 8.1 Hz), 7.29 (1H, t, J = 8.5Hz), 7.39-7.44 (1H, m), 7.66-7.70 (2H, m), 7.84 (1H, dd, J = 7.0, 1.9Hz), 8.25 (1H, s), 8.42 (1H, t, J = 5.1 Hz), 8.50 (1H, d, J = 2.0 Hz) 523.20 (3H, s), 3.92 (3H, s), 4.50 (2H, s), 4.51 (2H, d, J = 5.0 Hz), 5.15(2H, s), 5.33 (2H, s), 6.24 (1H, td, J = 6.7, 1.3 Hz), 6.37 (1H, d, J =9.0 Hz), 7.19 (1H, d, J = 8.0 Hz), 7.28 (1H, t, J = 8.4 Hz), 7.41-7.46(1H, m), 7.63 (1H, dd, J = 8.1, 2.2 Hz), 7.67 (1H, dd, J = 8.7, 1.1 Hz),7.75 (1H, dd, J = 6.7, 1.8 Hz), 8.24 (1H, s), 8.40 (1H, t, J = 5.1 Hz),8.44 (1H, d, J = 1.7 Hz) 53 3.21 (3H, s), 3.92 (3H, s), 4.49 (2H, s),4.51 (2H, d, J = 6.7 Hz), 5.01 (2H, s), 5.27 (2H, s), 6.43 (1H, dd, J =10.0, 5.4 Hz), 7.20-7.22 (2H, m), 7.25-7.30 (3H, m), 7.53-7.58 (1H, m),7.67 (1H, dd, J = 8.7, 1.3 Hz), 8.01 (1H, dd, J = 8.0, 3.2 Hz), 8.20(1H, s), 8.39 (1H, t, J = 5.2 Hz) 57 1.69 (4H, t, J = 3.3 Hz), 2.26-2.29(2H, m), 3.13-3.16 (2H, m), 3.22 (3H, s), 3.39 (3H, s), 4.46 (2H, s),4.51 (2H, s), 4.52 (2H, d, J = 4.9 Hz), 5.29 (2H, s), 7.17-7.22 (4H, m),7.28 (1H, t, J = 8.5 Hz), 7.67 (1H, d, J = 8.6 Hz), 8.22 (1H, s), 8.40(1H, t, J = 5.1 Hz) 58 1.89-1.92 (4H, m), 3.21 (3H, s), 3.43-3.46 (4H,m), 3.92 (3H, s), 4.51 (2H, s), 4.52 (2H, s), 5.13 (2H, s), 7.28 (1H,app.t, J = 8.5 Hz), 7.67 (1H, dd, J = 8.6, 1.3 Hz), 8.16 (1H, s), 8.35(2H, s), 8.37-8.39 (1H, m) 60 1.98 (3H, s), 3.18 (3H, s), 3.94 (3H, s),4.22 (2H, d, J = 4.7 Hz), 4.42 (2H, s), 5.20 (2H, s), 5.24 (2H, s), 7.17(4H, q, J = 6.6 Hz), 7.22 (1H, s), 7.33-7.41 (2H, m), 7.51 (1H, s), 8.10(1H, s), 8.15 (1H, t, J = 5.3 Hz), 9.73 (1H, s) 61 1.98 (3H, s), 3.19(3H, s), 3.82 (3H, s), 4.16 (2H, d, J = 5.7 Hz), 4.48 (2H, s), 5.21 (2H,s), 5.28 (2H, s), 7.06-7.11 (2H, m), 7.18-7.23 (5H, m), 7.48 (1H, d, J =8.6 Hz), 7.52 (1H, s), 8.18 (1H, s), 8.27 (1H, t, J = 5.7 Hz), 9.76 (1H,s) 64 4.25 (2H, d, J = 4.8 Hz), 5.07 (2H, s), 5.37 (2H, s), 6.20-6.24(1H, m), 6.39 (1H, d, J = 9.0 Hz), 7.25 (2H, d, J = 8.6 Hz), 7.27 (2H,d, J = 8.6 Hz), 7.40-7.46 (2H, m), 7.54-7.65 (2H, m), 7.76 (1H, dd, J =6.7, 1.9 Hz), 8.25 (1H, s), 8.51 (1H, t, J = 5.0 Hz), 9.80 (1H, s) 714.17 (2H, d, J = 5.8 Hz), 5.05 (2H, s), 5.07 (2H, s), 5.34 (2H, s),6.20-6.24 (1H, m), 6.39 (1H, dd, J = 9.8, 9.1 Hz), 7.19 (2H, d, J = 8.1Hz), 7.26 (2H, d, J = 8.2 Hz), 7.39-7.43 (1H, m), 7.58 (1H, s), 7.62(2H, d, J = 1.4 Hz), 7.76 (1H, dd, J = 6.4, 1.9 Hz), 7.93 (1H, s), 8.30(1H, t, J = 5.8 Hz), 9.88 (1H, s) 72 3.20 (3H, s), 4.22 (2H, d, J = 5.8Hz), 4.49 (2H, s), 5.07 (2H, s), 5.28 (2H, s), 6.20-6.24 (1H, m), 6.39(1H, d, J = 8.9 Hz), 7.23 (2H, d, J = 8.3 Hz), 7.26 (2H, d, J = 8.4 Hz),7.38-7.43 (1H, m), 7.63 (3H, s), 7.75 (1H, dd, J = 7.0, 1.9 Hz), 8.19(1H, s), 8.34 (1H, t, J = 5.8 Hz), 9.87 (1H, s). 73 3.16 (3H, s), 4.26(2H, d, J = 5.0 Hz), 4.42 (2H, s), 5.05 (2H, s), 5.24 (2H, s), 6.19-6.23(1H, m), 6.39 (1H, d, J = 8.9 Hz), 7.19-7.26 (4H, m), 7.38-7.42 (1H, m),7.56-7.63 (2H, m), 7.75 (1H, dd, J = 6.8, 2.1 Hz), 7.82 (1H, dd, J =7.6, 1.8 Hz), 8.13 (1H, s), 8.15 (1H, t, J = 5.1 Hz), 9.79 (1H, s) 743.19 (3H, s), 4.23 (2H, d, J = 5.7 Hz), 4.49 (2H, s), 5.07 (2H, s), 5.28(2H, s), 6.20-6.24 (1H, m), 6.39 (1H, d, J = 9.1 Hz), 7.22 (2H, d, J =8.4 Hz), 7.26 (2H, d, J = 8.3 Hz), 7.38-7.43 (1H, m), 7.53-7.57 (2H, m),7.62 (2H, d, J = 3.0 Hz), 7.75 (1H, dd, J = 6.9, 1.9 Hz), 8.19 (1H, s),8.31 (1H, t, J = 5.8 Hz), 9.86 (1H, s) 77 1.91 (4H, t, J = 6.52 Hz),3.18 (3H, s), 3.35 (4H, t, J = 8.6 Hz), 3.93 (3H, s), 4.21 (2H, d, J =4.9 Hz), 4.42 (2H, s), 5.09 (2H, s), 6.40 (1H, d, J = 8.7 Hz), 7.33-7.43(3H, m), 8.03 (1H, s), 8.05 (1H, d, J = 2.2 Hz), 8.16 (1H, t, J = 5.2Hz), 9.74 (1H, s) 79 1.89-1.92 (4H, m), 3.18 (3H, s), 3.45 (4H, t, J =6.7 Hz), 3.93 (3H, s), 4.21 (2H, d, J = 4.6 Hz), 4.42 (2H, s), 5.10 (2H,s), 7.33-7.41 (2H, m), 8.07 (1H, s), 8.15 (1H, t, J = 4.9 Hz), 8.33 (2H,s), 9.73 (1H, s) 80 1.89-1.93 (4H, m), 3.19 (3H, s), 3.44-3.47 (4H, m),3.82 (3H, s), 4.16 (2H, d, J = 5.7 Hz), 4.49 (2H, s), 5.14 (2H, s), 7.07(1H, t, J = 2.8 Hz), 7.09 (1H, s, J = 2.6 Hz), 7.48 (1H, dd, J = 11.4,3.2 Hz), 8.15 (1H, s), 8.27 (1H, t, J = 5.8 Hz), 8.31-8.34 (1H, m), 8.36(1H, s), 9.76 (1H, s) 83 1.90-1.94 (4H, m), 3.35 (4H, t, J = 6.6 Hz),3.94 (3H, s), 4.20 (2H, d, J = 4.4 Hz), 5.22 (2H, s), 6.43 (1H, d, J =8.6 Hz), 7.34-7.41 (2H, m), 7.47 (1H, dd, J = 8.6, 2.4 Hz), 8.10 (1H, d,J = 2.2 Hz), 8.18 (1H, s), 8.48 (1H, t, J = 5.0 Hz), 9.70 (1H, s) 862.50-2.57 (2H, m), 3.18 (3H, s), 3.69 (2H, t, J = 7.4 Hz), 3.87 (2H, t,J = 12.2 Hz), 3.94 (3H, s), 4.22 (2H, d, J = 4.7 Hz), 4.41 (2H, s), 5.15(2H, s), 7.37-7.41 (2H, m), 8.09 (1H, s), 8.14 (1H, t, J = 5.2 Hz), 8.41(2H, s), 9.73 (1H, s) 87 2.46-2.57 (2H, m), 3.18 (3H, s), 3.59 (2H, t, J= 7.3 Hz), 3.80 (2H, t, J = 8.9 Hz), 3.93 (3H, s), 4.22 (2H, d, J = 4.8Hz), 4.42 (2H, s), 5.14 (2H, s), 3.59 (1H, d, J = 8.6 Hz), 7.33-7.41(2H, m), 7.50 (1H, dd, J = 7.7, 2.3 Hz), 8.06 (1H, s), 3.59 (1H, d, J =2.2 Hz), 8.14 (1H, t, J = 5.3 Hz), 9.74 (1H, s) 88 2.51-2.57 (2H, m),3.19 (3H, s), 3.70 (2H, t, J = 7.3 Hz), 3.82 (3H, s), 3.88 (2H, t, J =13.1 Hz), 4.16 (2H, d, J = 5.7 Hz), 4.48 (2H, s), 5.19 (2H, s), 7.06(1H, d, J = 2.5 Hz), 7.09 (1H, s), 7.49 (1H, d, J = 8.3 Hz), 8.18 (1H,s), 8.27 (1H, t, J = 5.6 Hz), 8.45 (2H, s), 9.77 (1H, s)

Biological Methods

The ability of the compounds of formula (I) to inhibit plasma kallikreinmay be determined using the following biological assays:

Determination of the IC₅₀ for plasma kallikrein

Plasma kallikrein inhibitory activity in vitro was determined usingstandard published methods (see e.g. Johansen et al., Int. J. Tiss.Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol., 1992, 43, 1209;Sturzebecher et al., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Humanplasma kallikrein (Protogen) was incubated at 25° C. with thefluorogenic substrate H-DPro-Phe-Arg-AFC and various concentrations ofthe test compound. Residual enzyme activity (initial rate of reaction)was determined by measuring the change in optical absorbance at 410 nmand the IC₅₀ value for the test compound was determined.

Data acquired from this assay are shown in Table 10.

Determination of the Ki for Plasma Kallikrein

Plasma kallikrein inhibitory activity in vitro was determined usingstandard published methods (e.g. Johansen et al., Int. J. Tiss. Reac.1986, 8, 185; Shori et al., Biochem. Pharmacol., 1992, 43, 1209;Sturzebecher et al., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Humanplasma kallikrein (Protogen) was incubated at 25° C. with 10concentrations of the test compound and 8 concentrations of thefluorogenic substrate H-DPro-Phe-Arg-AFC spanning a range of at least½×Km to 5×Km. Residual enzyme activity (initial rate of reaction) wasdetermined by measuring the change in fluorescence at 410 nm. The Kivalue for the test compound was determined using the mixed-modelinhibition equation (based on Equation 3.2 in: RA Copeland, Evaluationof Enzyme Inhibitors in Drug Discovery, Wiley 2005) in GraphPad Prism.The mixed model equation includes competitive, uncompetitive andnoncompetitive inhibition as special cases and the parameter of Alpha toindicate mechanism of inhibition.

Data acquired from this assay are shown in Table 11.

Selected compounds were further screened for inhibitory activity againstthe related enzyme KLK1. The ability of the compounds of formula (I) toinhibit KLK1 may be determined using the following biological assay:

Determination of the IC₅₀ for KLK1

KLK1 inhibitory activity in vitro was determined using standardpublished methods (see e.g. Johansen et al., Int. J. Tiss. Reac. 1986,8, 185; Shori et al., Biochem. Pharmacol., 1992, 43, 1209; Sturzebecheret al., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Human KLK1(Callbiochem) was incubated at 25° C. with the fluorogenic substrateH-DVal-Leu-Arg-AFC and various concentrations of the test compound.Residual enzyme activity (initial rate of reaction) was determined bymeasuring the change in optical absorbance at 410 nm and the IC₅₀ valuefor the test compound was determined.

Data acquired from this assay are shown in Table 10.

Selected compounds were further screened for inhibitory activity againstthe related enzyme FXIa. The ability of the compounds of formula (I) toinhibit FXIa may be determined using the following biological assay:

Determination of the % Inhibition for FXIa

FXIa inhibitory activity in vitro was determined using standardpublished methods (see e.g. Johansen et al., Int. J. Tiss. Reac. 1986,8, 185; Shori et al., Biochem. Pharmacol., 1992, 43, 1209; Sturzebecheret al., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Human FXIa (EnzymeResearch Laboratories) was incubated at 25° C. with the fluorogenicsubstrate Z-Gly-Pro-Arg-AFC and 40 μM of the test compound (oralternatively at various concentrations of the test compound in order todetermine IC₅₀). Residual enzyme activity (initial rate of reaction) wasdetermined by measuring the change in optical absorbance at 410 nm andthe IC50 value for the test compound was determined.

Data acquired from this assay are shown in Table 10.

Factor XIIa inhibitory activity in vitro was determined using standardpublished methods (see e.g. Shori et al., Biochem. Pharmacol., 1992, 43,1209; Baeriswyl et al., ACS Chem. Biol., 2015, 10 (8) 1861; Bouckaert etal., European Journal of Medicinal Chemistry 110 (2016) 181). HumanFactor XIIa (Enzyme Research Laboratories) was incubated at 25° C. withthe fluorogenic substrate H-DPro-Phe-Arg-AFC and various concentrationsof the test compound. Residual enzyme activity (initial rate ofreaction) was determined by measuring the change in optical absorbanceat 410 nm and the IC50 value for the test compound was determined.

Data acquired from this assay are shown in Table 10.

TABLE 10 IC₅₀ % Inhibition IC₅₀ (human @ 40 μM IC₅₀ (human KLK1) IC₅₀(human (human (human Example Number PKal) nM nM FXIa) nM FXIa) FXIIa) nMReference Example A 698 >10000 >40,000 0 Reference Example B8.7 >10000 >40,000 8 >40,000 Reference Example C 2580 >10000 >40,000 3Reference Example D 3.3 >40000 >40,000 0 >40,000 Reference Example E0.6 >40000 >40,000 28 >40,000 Reference Example F 6.8 >40000 >40,000 14Reference Example G 742 >10000 >40,000 10 Reference Example H1.1 >40,000 >40,000 >40,000 Example 7 from 2034 >40,000 >40,000 >40,000WO 2013/111108 Reference Example I 2017 >40,000 >40,000 >40,000 Example14 from 110 >4000 >40,000 >40,000 WO 2013/111108 Example 27 from731 >40000 >40,000 >40,000 WO 2013/111108 Reference Example J2869 >40,000 >40,000 >40,000 1 26.1 >40,000 >40,000 >40,000 42303 >4000 >40,000 >4,000 5 2.0 >40000 >40,000 >40,000 63.2 >4000 >40,000 2 >4,000 7 18.0 >40000 >40,000 >40,000 8162 >4000 >40,000 >4,000 10 2450 >40000 >40,000 >40,000 1135.0 >40000 >40,000 >40,000 13 2952 >4000 >40,000 >4,000 16187 >40000 >40,000 >40,000 17 143 >40000 >40,000 >40,000 203223 >40000 >40,000 0 >40,000 22 4.9 >40000 >40,000 5 >40,000 261760 >40000 >40,000 >40,000 27 775 >40000 >40,000 >40,000 28163 >40000 >40,000 >40,000 29 217 >40000 >40,000 >40,000 306.7 >40000 >40,000 7 >40,000 31 462 >40000 >40,000 >40,000 34709 >40000 >40,000 35 1.7 >40000 >40,000 5 >40,000 37 283 >40000 >40,0007 >40,000 38 301 >4000 >40,000 >4,000 39 0.6 >4000 3700 91 >4000 400.4 >40000 >40000 20 >40000 41 149 >4000 >40,000 >4,000 423.6 >4000 >40,000 >4,000 43 0.6 >4000 >40000 27 >4,000 448.8 >80000 >40000 32 >40000 49 15.9 >4000 >40,000 >4000 5121.3 >4000 >40,000 >4,000 52 6.4 >4000 >40,000 >4,000 531.7 >40000 >40,000 5 >40,000 57 27.9 >40,000 >40,000 >40,000 5857.0 >40000 8500 >40,000 60 0.9 >40000 4700 90 >40000 611.7 >4000 >40,000 >4000 64 0.6 >4000 >40,000 >4000 71 0.3 >40004600 >4000 72 0.7 >4000 10600 53% >4000 Inhibition @ 12.7 μM 7323.1 >4000 >40,000 >4000 74 17.6 >40000 >40000 8 >40000 77 1.4 >40000235 100 >40000 Reference example K 2.0 >40000 76 >40000 79 1.5 >40000127 96 >40000 80 10.6 >4000 779 >4000 83 0.3 >40,000 230 >40,000 861.7 >40000 477 99 >40000 87 0.8 >40000 161 >40000 88 8.3 >40000 4880>40000

TABLE 11 Example Number Ki Alpha Reference Example B  6.7 nM 48Reference Example H 0.52 nM 108 Example 14 from  139 nM 4 × 10¹⁷ WO2013/111108 22  1.9 nM 29 39 0.26 nM 1.7 40 0.10 nM 2.2 60 0.30 nM 1.672 0.16 nM 6.0 77 0.17 nM 4.2 79 0.38 nM and 0.23 nM (two 7.08 and 2.16(two individual determinations) individual determinations) 80  2.4 nM14.8 83 0.53 nM 2.24 86 0.28 nM 2.78 88  2.9 nM 1 × 10²²

Determination of Enzyme Selectivity

Human serine protease enzymes plasmin, thrombin and trypsin were assayedfor enzymatic activity using an appropriate fluorogenic substrate.Protease activity was measured by monitoring the accumulation ofliberated fluorescence from the substrate over 5 minutes. The linearrate of fluorescence increase per minute was expressed as percentage (%)activity. The Km for the cleavage of each substrate was determined bystandard transformation of the Michaelis-Menten equation. The compoundinhibitor assays were performed at substrate Km concentration andactivities were calculated as the concentration of inhibitor giving 50%inhibition (IC₅₀) of the uninhibited enzyme activity (100%).

Data acquired from these assays are shown in Table 12 below:

TABLE 12 (Selectivity data) Example IC50 (nM) Number Plasmin ThrombinTrypsin 6 >40000 >40000 >40000 30 >40000 >40000 >4000035 >40000 >40000 >40000 37 >40000 >40000 >40000 39 31200 19300 >4000040 >40000 >40000 >40000 43 >40000 >40000 >40000 53 >40000 >40000 >4000072 >40000 39200 >40000 74 >40000 >40000 >40000 79 12010 7310 >40000

Solubility Data

Solubility was determined in water and 0.1N HCl (aq). Test compoundswere incubated at 1 mg/mL for 24 hrs at 37° C. on a shaking platform(500 rpm). Samples were taken at 1, 4 and 24 hrs and centrifuged at15,000 g for 10 min. Test compound concentration in the supernatant wasdetermined by LCMS against a standard curve.

Example 0.1N HCl (aq) Number (mg/mL) Water (mg/mL) 22 0.90 0.06 30 0.940.29 35 0.04 0.02 39 0.019 0.007 72 0.046 0.046 79 0.924 0.093 86 0.050.001

In Vitro ADME Data

In vitro permeability was determined using the Caco-2 model for oralabsorption. The methodology was adapted from standard published methods(Wang Z, Hop C. E., Leung K. H. and Pang J. (2000) J Mass Spectrom35(1); 71-76). The Caco-2 monolayers were established in a Biocoat™ HTSfibrillar collagen 24 well multiwell insert system (1.0 μm, PETmembrane, Corning 354803) in which 200,000 cells were seeded into eachinsert and maintained over 3 days before being utilised in thepermeability assay. For the assay, 50 μM test compound is added to theapical side of the inserts and incubated for 1 hour at 37° C. on ashaking platform (120 rpm). Apical to basolateral transport wasdetermined by measuring the test article in both compartments by LCMSfollowing the 1 hour incubation. The integrity of the Caco-2 monolayerswas confirmed by two methods, (i) comparison of pre- and post-experimenttransepithelial electrical resistance (TEER) and, (ii) assessment ofLucifer Yellow flux.

The intrinsic clearance was determined using standard published methods(Obach R S (1999) Drug Metab Dispos 27(11); 1350-135). Rat or humanliver microsomes (0.5 mg/mL; Corning) were incubated with 5 μM testcompound at 37° C. on a shaking platform (150 rpm). Samples were takenat 0, 6, 12, 18, 24 and 60 min and test compound concentrations weredetermined by LCMS against a calibration curve. The intrinsic clearance(Clint) was calculated using methodology described by Obach (Obach R Set al. (1997) J Pharmacol Exp Ther 283: 46-58.) or Lau (Lau Y Y et al(2002). Drug Metab Dispos 30: 1446-1454).

Human liver microsome rat liver (Clint microsome μL/min/mg (ClintμL/min/mg Caco-2 Example Number protein) protein) (Papp ×10⁻⁶ cm/s)Reference 25 94 12 Example H Example 7 from 58 62 8 WO 2013/111108Reference 77 153 15 Example I Example 27 from 71 72 7 WO 2013/111108Reference 110 187 12 Example J 1 33 52 28 5 3 6 2 6 42 30 17 7 22 8 1022 25 68 25 30 20 22 24 35 24 15 7 37 48 73 20 39 29 19 6 40 22 47 5 428 11 4 43 10 5 2 44 162 101 17 49 18 36 6 51 30 25 3 52 16 8 5 53 104 7713 58 26 60 90 114 25 61 55 132 22 64 35 94 6 71 17 17 1 72 32 72 6 73 474 2 77 29 82 28 Reference 3 Example K 79 4 23 19 80 14 54 23 83 23 86 435 16 87 4

Plasma Protein Binding (PPB) and Predicted Clearance

The fraction unbound in plasma was determined using ThermoScientific™Pierce™ Rapid Equilibrium Dialysis Technology (Single-Use plate withinserts, 8K MWCO). 5 μM test compound was spiked into human or ratplasma (300 μL) and dialysed against 146.5 mM phosphate buffer (500 μL)for 5 hrs at 37° C., shaking at 1200 rpm. Reference samples from thenon-dialysed plasma were taken before the incubation to enable anassessment of recovery. Test compound concentrations were determined inplasma and buffer compartments by LCMS against a calibration curve. Thefraction unbound in plasma was determined using standard methodology(Waters N J et al (2008) J Pharm Sci 97(10); 4586-95). Results arepresented as percent plasma protein bound (% PPB).

The predicted plasma clearance (Clp) is calculated using thewell-stirred model (Rowland M, Benet L Z, and Graham G G. Clearanceconcepts in pharmacokinetics. J Pharmacokinet Biopharm. (1973)1:123-136.), one of several models that can be used to extrapolate thein vitro data. The model assumes instantaneous and complete mixing ofdrug within the liver and is a function of intrinsic clearance, hepaticblood flow and free fraction of drug in the blood. The predicted plasmaclearance in mL/min/kg is presented as a percentage of hepatic bloodflow (LBF).

Predicted Example % PPB Predicted in vivo in vivo rat Number (human) %PPB (rat) human Clp (% LBF) Clp (% LBF) Reference 84 87 14 26 Example H5 77 64 3 5 6 87 95 24 6 22 92 >99 7 <1.6 30 82 97 12 1 35 96 99 7 1 3792 95 16 11 39 78 89 21 5 40 76 87 17 14 43 88 92 8 2 53 90 96 35 10 6091 97 35 12 61 92 96 4 15 64 92 91 19 33 72 90 94 14 12 77 97 >99 3 <2.079 91 95 1 3 80 92 96 4 6 86 90 97 2 3

Pharmacokinetics

Pharmacokinetic studies of the compounds in Table 13 were performed toassess the pharmacokinetics following a single oral dose in maleSprague-Dawley rats. Two rats were given a single po dose of 5 mL/kg ofa nominal 2 mg/mL (10 mg/kg) composition of test compound in vehicle.Following dosing, blood samples were collected over a period of 24hours. Sample times were 5, 15 and 30 minutes then 1, 2, 4, 6, 8 and 12hours. Following collection, blood samples were centrifuged and theplasma fraction analysed for concentration of test compound by LCMS.Oral exposure data acquired from these studies are shown below:

TABLE 13 Oral exposure data Example Dose po Cmax Number Vehicle (mg/kg)(ng/mL) Tmax (min) Reference 10% DMSO/10% 9.5 351 60 Example Bcremophor/80% SWFI Reference 10% DMSO/10% 10.5 1534 180 Example Dcremophor/80% SWFI Reference 10% DMSO/10% 5.5 397 30 Example Ecremophor/80% SWFI  6 10% DMSO/10% 2.2 1802 30 cremophor/80% SWFI 22 10%DMSO/10% 9.1 1025 60 cremophor/80% SWFI 30 10% DMSO/10% 4.3 756 38cremophor/80% SWFI 39 10% DMSO/10% 8.0 187 30 cremophor/80% SWFI 77 10%DMSO/10% 7.0 845 90 cremophor/80% SWFI 79 10% DMSO/10% 11.3 807 45cremophor/80% SWFI 86 10% DMSO/10% 5.0 981 30 cremophor/80% SWFI

The invention claimed is:
 1. A compound that is:

or a pharmaceutically acceptable salt or solvate thereof.
 2. Thecompound of claim 1 that is:

.
 3. The compound of claim 1 that is a pharmaceutically acceptable saltof


4. A pharmaceutical composition comprising a compound, orpharmaceutically acceptable salt or solvate thereof, of claim 1 and apharmaceutically acceptable carrier, diluent or excipient.